Download Infections Associated With Implanted Medical Devices.

CHAPTER
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45
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I nfections associated with
i mp lante med
dical demces
Christopher J. Crnich, Nasia Safdar and Dennis G. Maki
This chapter provides an overview of the risk of infection associated
with the use of the most important implanted medical devices (see
Table 45.1), their clinical features, pathogenesis, epidemiology, diagnosis and treatment and, perhaps most importantly, strategies for their
prevention.
GENERAL ASPECTS OF PATHOGENESIS
Implantation of prosthetic material evokes a host response,
which intrinsically increases the risk of infection. Animal
models have shown that the inoculum needed to establish
infection is greatly reduced in the presence of a foreign body.'
The characteristics of the implanted device and the material
from which it is manufactured, the likelihood that the device
might be exposed to micro-organisms, the intrinsic virulence
of the involving organisms and the capacity of the host to resist
infection all contribute to the overall risk of device related
infection.
`Biomaterial' is a generic term for the material from which
a medical device, manufactured for the distinct purpose of
i mplantation in the human body, is constructed. Most devices
are constructed of hydrocarbon polymers, which can now be
engineered with predictable mechanical properties. Biomaterial
in contact with deep tissues can have one or more physiologic
effects: 2
the biomaterial releases chemicals toxic to contiguous tissue;
the biomaterial is non-toxic, but unable to resist the inflammatory response its presence elicits, and the material is
absorbed over time (e.g. chromic gut sutures);
the biomaterial is non-toxic and unaffected by the inflammatory response, avoiding absorption by the body, but
elicits chronic inflammation, resulting in encapsulation of
the device (e.g. hip arthroplasty) or local thrombosis (e.g.
vascular catheters); ,4
the biomaterial is both non-toxic and biocompatible, and
well tolerated by tissue, resulting in adhesive bonds that
stabilize the device and attenuate the inflammatory reaction
(e.g. bioactive glass-ceramics and bioactive composites 5).
Almost all implanted medical devices in use today fall into
the third category. Development of a biologically totally inert
material that does not induce a host response and is nonthrombogenic remains the `holy grail' of biomaterials research.
The ensuing host-foreign body reaction plays an integral
role in promotion of implant infection by distorting the local
immune response and coating (`processing') of the surface by
matrix proteins. 6 Animal models show striking derangement
of the immune response in the peri-implant environment, most
notably in phagocytosis. 1,7 Neutrophils recovered from the
surface of foreign bodies show greatly reduced levels of
granule-associated bactericidal enzymes and oxidative burstdependent bactericidal activity. 1,7,8
The presence of a foreign body not only perturbs local
i mmune dysfunction but also provides an altered surface to
which bacteria can more readily adhere and form a complex
microenvironment, or biofilm. While non-specific physiochemical forces, such as surface tension, electrostatic forces,
hydrophobic interactions and van der Waal's forces mediate
the initial microbial adherence to a foreign body, 9 durable
adherence is also influenced by specific host-protein-microbial interactions.
After placement, vascular catheters are rapidly coated by
host proteins, including albumin, fibrinogen, fibrin, fibronectin
and platelets; 10-12 a similar process probably occurs with other
implanted devices. Studies with Staphylococcus aureus have
identified specific microbial fibronectin- 13-16 and fibrinogenbinding surface proteins, 15,17,18 and other proteins with broader
specificity that can bind fibronectin as well as fibrinogen, vitronectin, thrombospondin and bone sialoprotein. 19,2o Direct
support for the importance of these bacterial surface proteins
comes from both in-vitro and animal modeIs: 21 .22 knockout
strains of Staph. aureus that are deficient in fibronectin-binding
surface proteins show a markedly reduced capacity to bind to
polymethylmethacrylate (PMMA) coated slides in vitro 22 or to
traumatized heart valves in a rat model.21 Moreover, strains of
CHAPTER 45
I NFECTIONS ASSOCIATED WITH IMPLANTED MEDICAL DEVICES
Staph. aureus deficient in the gene for production ,of the fib-
rinogen-binding surface protein lack the ability to adhere to
PMMA-coated slides that are covered with fibrinogen. 18 The
capacity to adhere is regained when the gene is restored to the
knockout strain.
Coagulase-negative staphylococci also have the ability to
bind fibronectin, although with less avidity than Staph.
aureus. 15 16 In contrast, fibrinogen does not appear to be a
major receptor for binding of coagulase-negative staphylococci
to implant surfaces, 16 although other surface binding proteins
unique to this micro-organisms have been reported A polysaccharide capsular adhesin that mediates the attachment to
uncoated polysterene catheters has been identified, and antibodies to this epitope have been shown to inhibit binding to
silicone catheters and prevent catheter-related infection in a
rabbit model
Once bound to an implanted device, most micro-organisms that cause device-related infection are able to produce
an extracellular polysaccharide matrix . 25 The combination
of host proteins in intimate association with microcolonies of
the infecting organism, embedded in massive quantities of
exoglycocalyx, comprises a unique microecosystem, the
biofilm. 26.27 Biofilms can be found almost universally on
infected implanted materials of all types, 26 and have been
best characterized with:
3
.23
. 24
Gram-positive
bacteria, especially Staph. aureus, 28
Staphylococcus epidermidis,29 and Enterococcus faecahs; 3 o
Gram-negative bacilli, such as Escherichia coli, 31 Pseudomonas
aeruginosaM and Burkholderia cepacia; 32
yeasts, such as Candida albicans. 33
Organisms within a biofilm are uniquely adapted to extreme
environments and form a nidus of chronic infection on the
surface of the implanted device from which planktonic phase
organisms are released, producing signs and symptoms of
infection.
Biofilms greatly facilitate surface adherence, protect the
micro-organism and allow its survival, even under intense
attack from the immune system and high concentrations of
antimicrobial drugs. Several mechanisms appear to be responsible.
tonic, rapidly growing phase encountered in infections unrelated to implanted devices.
The extraordinary capacity of the biofilm to produce
refractory infection can be seen in in-vitro experiments: studies have shown that concentrations of a bactericidal antibiotic
100 to 1000 times those effective against the planktonic
phase of the organism (the minimal inhibitory concentration
or MIC) do not kill the micro-organisms within a biofifimm 38
Thus, while antimicrobial therapy is often effective in resolving the acute features of device-associated infection, such as
local inflammation and fever, antimicrobial therapy alone
rarely kills the indolent sessile organisms within the deepest
layers of an implant-associated biofilm. For these reasons,
the management of most implanted device-related infections
requires removal of the infected device as well as appropriate
antimicrobial therapy.
I NFECTIONS ASSOCIATED WITH
ORTHOPEDIC DEVICES
EPIDEMIOLOGY
Over seven million orthopedic procedures were performed in
the USA in 1996, including 500 000 total knee arthroplasties
and total hip arthroplasties. 39 The site of prosthetic joint
implantation, characteristics of the implant, and events surrounding the operation have a profound impact on the risk of
infection.
Rates of deep infection after total hip arthroplasty range
from c. 0.5 to 1.5% at most centers; 4o• 41 rates of infection with
total knee arthroplasty appear to be somewhat higher, in the
range of 0.8-2.5% (Table 45.1). 41-43 The risk of infection
appears to be highest in the first 2-3 years after surgery: combined rates of hip and knee prosthetic infection are 6.5 per
1000 joint years in the first year after surgery, 3.2 per 1000
during the second postoperative year and 1.4 per 1000 in the
total years thereafter.44 Rates of infection with other prosthetic
joint implants have been less well characterized but average
1 % for shoulders,45 2.4-6.0% for ankles and wrists46 47 and as
high as 7-9% for elbows. 46
The characteristics of the artificial joint clearly influence the
risk of infection. Use of metal-on-metal hinged knee prostheses have been shown to be associated with a risk of infection
20 times higher than encountered with the modular metal-onpolyethylene prosthetic joints most widely used today. 48 Host
factors associated with an increased risk of postoperative infection of the prosthesis include rheumatoid arthritis, 41,4 a- diabetes mellitus, 51 malignancy, 52 concurrent corticosteroid use, 53
hemophilia54 and revision arthroplasty. Other factors that may
increase the risk of infection, such as obesity 55 and active
urinary tract infection at the time of surgery, have been less
rigorously evaluated.
>
1. Micro-organisms encased in a biofilm are resistant to phagocytosis,34 and there is evidence that antimicrobial oxidants
produced by phagocytic cells are inactivated in the superficial layers of a biofilm.26
2. Antimicrobial drugs penetrate biofilms poorly 35,36 and lose
activity in the acidic and anaerobic environment of the
deepest layers of a biofilm . 27
3. Micro-organisms in a biofilm are in a sessile, or slowgrowing phase of growth that further enhances resistance to
antimicrobials, most of which are most effective against
rapidly multiplying organisms. 37
4. Micro-organisms in a biofilm exhibit unique phenotypic features, 27 expressing genes that are not expressed in the plank-
SO
I NFECTIONS ASSOCIATED WITH ORTHOPEDIC DEVICES
I
Table 45.1 Risk of infection with the implanted medical devices i n widest clinical use
Device
Approximate risk of infection
over the lifetime of the device
Orthopedic devices
Total joint prostheses
Hip
Knee
Elbow, ankle, and wrist
0.5-1.5
0.8-2.5
1 -9
Cardiovascular devices
Prosthetic heart valves
Mechanical
Bioprosthetic
Coronary stents
Pacemakers and implantable cardiac defibrillators
Left ventricular assist devices
I mplanted artificial heart
-5
-6
<0.01
1 -7
1 5-70
Unknown
I ntravasculardevices
Short-term vascular catheters
Peripheral venous catheters and needles
Arterial catheters
Central venous catheters
Temporary hemodialysis catheters
Long-term devices
Cuffed and tunneled central venous (Hickman and
Broviac) catheters
Peripheral inserted central catheters
Subcutaneous central ports
Tunneled and cuffed hemodialysis catheters
Vascular Gore-tex and Dacron arterial grafts
0.2-0.4
1 -2
3-4
13-18
1 8-22
0.5-2
4-6
4-9
1 -5
Neurosurgical devices
Ventriculoperitoneal, ventriculoatrial and lumboperitoneal
shunts
Ventriculostomy catheters
Intra-arterial coils
2-9
-10
<0.01
UrologicaVrenal devices
Urethral catheters
Ureteral stents
Peritoneal dialysis catheters
Penile implants
1 0-50
-7
20-50
1 -3
Miscellaneous
Breast implants
Intra-abdominal mesh
PATHOGENESIS
Several staging systems have been proposed for prosthetic joint
sepsis but consensus is lacking. The most widely accepted
system is that formulated originally by Coventry 56 and modified by Gillespie. 5 '
Stage 1 infections are defined as those occurring within 1
month of surgery; patients with stage 1 infections typically
present with signs of sepsis as well as local signs of infection,
with local erythema and wound discharge. The organisms most
commonly recovered from stage 1 infections derive from the
-3
2-8
patient's skin, bacteria in operating room air, or the skin of
members of the surgical team. 58, s 9
Stage 2 infections are defined as those that occur after 1
month but within 2 years of surgery. These infections are also
thought to derive from the introduction of organisms of low
pathogenicity, such as coagulase-negative staphylococci and
Propionibacterium sp., at the time of surgery. Patients typically
exhibit gradual impairment of prosthetic function, (i.e. early
loosening of the prosthesis and increasing joint pain).
Stage 3 infections are arbitrarily defined as infections that
occur more than 2 years after surgery and are assumed to
derive from hematogenous seeding of the joint.
577
B
I CHAPTER 45
I NFECTIONS ASSOCIATED WITH IMPLANTED MEDICAL DEVICES
There are limitations with the above classification. The
Coventry system fails to take into account the possibility of
hematogenous seeding of the newly placed joint that might
occur from intravascular device-related bloodstream infections
as well as from intercurrent urinary tract or other remote infections. 6 °-62 Furthermore, the capacity of certain micro-organisms, such as coagulase-negative staphylococci to be present
in the joint for prolonged periods before manifesting signs of
overt infection is well known,63 and an arbitrary cutoff of 2
years to define local versus hematogenous infection fails to take
this into account. Nevertheless, most stage 3 infections behave
differently than stage 2 infections in that patients typically have
completely normal joint function then abruptly develop acute
pain and inflammation of the joint, in contrast to the gradual
decline in function seen with most stage 2 infections.
While definitively identifying the source of a prosthetic joint
infection may be difficult, several lines of evidence suggest that
the vast majority derive from contamination of the wound at
the time of surgery.
1. The risk of prosthetic joint infection is highest in the perioperative period. 44
2. Most late infections are caused by Staph. aureus and coagulase-negative staphylococci, 44 which are acquired from skin
of the patient or members of the operating team at the time
of surgery.
3. Operating theaters that provide ultrafiltered air, to reduce
airborne microbial counts to <5 colony forming units
(cfu)/m 3 , have 10-60% lower rates of infection than operating rooms that do not employ such systems. 64,65
4. Studies of perioperative antibiotic prophylaxis have shown
a 64-85% reduction in rates of prosthetic joint infection, 57,63,64,66 with the benefit of prophylaxis becoming ever
greater the longer the period after surgery. 63
5. Studies that have rigorously attempted to identify the source
Coagulase-negative
staphylococci
Staphylococcus
aureus
of prosthetic joint infections have found that hematogenous
seeding appears to account for only 7-11% of all cases. 67-69
MICROBIOLOGY
Staph. aureus and coagulase-negative staphylococci predominate in prosthetic joint infections (Figure 45.1); infections with
other Gram-positive organisms, such as streptococci and enterococci, are less common. 44 Infections caused by aerobic
Gram-negative bacilli usually occur in association with Grampositive organisms (mixed infections), 44 and in this situation
probably reflect gross intraoperative contamination of the surgical wound or, perhaps, postoperative invasion of microorganisms through surgical drains. Hematogenous seeding is
more likely when organisms are isolated in pure culture,
although direct inoculation is still possible. The microbial
profile of prosthetic joint infections has been remarkably stable
over time, 44 which suggests that the pathogenesis of infection
in both early and late infection is similar (i.e. most originate in
the operating theater, even most late-onset infections).
DIAGNOSIS
Patients with early postoperative prosthetic joint infection
usually show impressive signs and symptoms of joint inflammation: severe pain and limited range of motion, usually in
association with erythema of the surgical wound, with or
without discharge. Signs of systemic sepsis, with fever, tachycardia and even shock, may be present, depending on the virulence of the infecting organism(s) (e.g. Staph. aureus or
Gram-negative bacilli). Patients with late hematogenous infection often show a similarly fulminant course complicating recent
skin or respiratory tract infection, or dental manipulation. This
23%
Polymicrobial
Gram-negative bacilli
Streptococci
8%
Unknown
8%
Anaerobes
Enterococci
Others
2%
Fig.45.1 Microbial profile of prosthetic joint infections, based on 1033 documented
cases seen at the Mayo Clinic from 1969 to 1991.549
I NFECTIONS ASSOCIATED WITH ORTHOPEDIC DEVICES
pattern was highlighted in a recent report where 16 of 59
patients with orthopedic devices and documented nosocomial
Staph. aureus bacteremia developed prosthetic device infection
0-65 days (median 3 days) after the onset of bacteremia. 70
Patients with stage 2 infections often follow an indolent
course, characterized by increasing pain and slowly deteriorating joint function that may or may not be associated with
loosening of the prosthesis radiographically. Most are afebrile.
No single test or clinical finding is pathognomonic of infection, thus it is necessary to interpret the results of multiple tests
and, especially, to obtain joint aspirates or deep operative cultures off antibiotics.
Routine laboratory studies usually, but not always, show
leukocytosis. 71 The erythrocyte sedimentation rate (ESR) is
elevated in most cases but is a non-specific finding, with a sensitivity ranging from 54 to 82% and specificity 65-85%." -73
C-reactive protein (CRP) appears to be a better dagnostic test,
with reported sensitivities of 80-96% and specificities ranging
from 93 to 100%, respectively. 73,74 CRP is particularly useful
in the early postoperative period as the level should normalize
within 2-3 weeks after surgery; 75-" persistent elevation should
prompt suspicion of indolent infection. Finally, the combined
use of the ESR and CRP, when both are normal, virtually rules
out prosthetic joint infection. 74
Plain radiographs are usually normal in early postoperative
and hetnatogenously derived infections. Loosening of the joint
prosthesis may be seen with chronic infection but this finding
is not specific. 78 Periosteal reaction or scalloping of the bone
is more specific for infection but is often absent in chronic
infections,78,79 especially those caused by coagulase-negative
staphylococci. Ultrasound may be useful for identifying
hematomas in the early postoperative period as well as guiding
needle aspiration of a joint suspicious for infection.
Numerous studies have evaluated nuclear imaging modalities for the diagnosis of prosthetic joint infection.
Unfortunately, most studies were limited by bias introduced
through patient selection, lack of randomization, the use of
multiple sequential scans, 80 and, especially, lack of a rigorous
definition infection. Published studies have reported sensitivities of 38-68% for technetium/gallium radionuclear scanning, 81-83 72-83% for technetium/indium " 1-labelled
granulocyte scanning, 81,84 and 64-100% for indium 111 -labeled
IgG scanning. 84-s6 Specificity is not much better, ranging from
40 to 100% for the above three tests. 81-86
Microbiologic confirmation of infection remains the gold
standard for the diagnosis of prosthetic joint infection and
should always be sought. Blood cultures are positive in only
20% of prosthetic joint infections and are rarely positive in the
absence of systemic signs of sepsis. Superficial swabs of surgical wounds or draining sinuses are unreliable for identifying
the specific organism(s) infecting the prosthetic joint. 87 The
failure of non-invasive tests to be able to reliably confirm the
presence of infection requires imaging guided aspiration of the
suspect joint or intraoperative sampling. The sensitivity of pre
operative joint aspiration is >80% (range 50-100 6/0) 73,83,88,89
and recovery of an organism usually is indicative of infection
I
(specificity, 92 to 100%).' 3'$3.88,89 Concurrent antimicrobial
therapy clearly reduces the yield of joint aspiration culture and
its use should be deferred until all appropriate microbiological studies have been completed.
Intraoperative Gram stain has been advocated by some as
a method for rapidly identifying or ruling out the presence of
prosthetic joint infection. Unfortunately, the Gram stain is positive in less than one-third of prosthetic joint infections and is
almost certainly less accurate with intercurrent antibiotic
therapy. 73,83,90,91 Intraoperative cultures have the highest yield,
provided that antibiotic therapy is withheld until immediately
after obtaining specimens for culture. Tissue samples, rather
than swabs, are preferable and obtaining multiple samples
(three or more) improves the specificity. 90 Sampling from the
sonicated removed implant may further increase yield by the
release of biofilm organisms. 92 It is imperative that multiple
samples be inoculated on solid media in the microbiology lab
rather than cultured solely in liquid media: multiple colonies
growing on solid media almost always represent true infection,
whereas microbial growth only in broth is most often indicative of contamination.
TREATMENT
Management of a patient with confirmed prosthetic joint infection requires careful consideration of the stage of the infection
(early postoperative, chronic or acute hematogenous infection),
the characteristics of the infecting organism, the patient's comorbidities and life expectancy.
Surgical management
Historically, infection of a prosthetic joint has been most effectively managed with two-stage exchange arthroplasty: 93-95 surgical debridement with removal of the infected prosthetic
device and all cement, followed by a prolonged period of parenteral antimicrobial therapy-6-12 weeks or longer-during
which time the joint is immobilized, increasingly with the use
of an antibiotic-impregnated spacer;96,97 when all clinical signs
of infection have resolved and, ideally, the ESR and CRP have
normalized, a new prosthetic device is implanted, often with
the use of antibiotic-impregnated cement" or a cementless
prosthesis." Multiple intraoperative specimens are cultured
and if persistent infection is found parenteral antibiotic therapy
is continued postoperatively, guided by resolution of the clinical features of infection and laboratory measures of inflammation (ESR and CRP). With this approach, long-term
eradication of a prosthetic joint infection can be achieved in
87-96% of infected total hip arthroplasties 100-103 and in
83-96% of infected total knee arthroplasties. 96,97,102,104
Obviously, this approach is costly, both for the healthcare
system and the patient, who must endure prolonged immobilization, deconditioning and not one but two major operations.
This has led to three alternative approaches to management:
initial irrigation and debridement with retention of the pros-
579
80
I CHAPTER 45
I NFECTIONS ASSOCIATED WITH IMPLANTED MEDICAL DEVICES
thetic device, followed by prolonged antimicrobial therapy;
one-stage exchange arthroplasty followed by antimicrobial
therapy; and the use of indefinite antimicrobial suppression.
Irrigation and debridement with retention of the prosthetic
device has been best evaluated with early postoperative infections and has shown encouraging results. 105,106 I n contrast,
attempts to salvage the prosthesis in patients who have late
infections or evidence of ongoing infection for more than 5
days have shown failure rates ranging from 62% to
86%. 104,107-110 Debridement with retention of the prosthesis
may achieve rates of success of about 70% in carefully selected
patients who are in the early postoperative period (< one
month): 107,111-113 (1) patients must have a hyperacute presentation (< 2-5 days), 1 05,108,110 as shown in one study where the
failure with debridement and retention greatly increased if
symptoms of infection had been present for more than two
days (RR = 4.2, 95% confidence interval = 1.6-10.3);108 (2)
the prosthesis must be stable without radiologic evidence of
loosening; (3) the patient must be willing to comply with prolonged antimicrobial therapy for 3-6 months or longer; and
(4) most importantly, the infecting micro-organism must be
highly susceptible to both parenteral and oral antibiotics, such
as a-hemolytic or group A streptococci.
Published studies of one-step exchange arthroplasty have
reported success rates that exceed 80%, 114-118 which
approaches the rate seen with the traditional two-step exchange
arthroplasty. However, almost all of the published experiences
are case series of highly selected patients (i.e. prosthetic infections caused by Gram-negative bacilli or methicillin-resistant
Staph. aureus (MRSA) were excluded). Notably, Hanssen et
al found that only 11% of patients presenting with prosthetic
joint infection at their institution met criteria for one-step
exchange arthroplasty. 119 Moreover, a study of 118 unselected infected total knee arthroplasties found that one-step
exchange arthroplasty was successful in only 63% of cases, 120
and a retrospective analysis from the UK revealed that the rate
of recurrent infection after one-stage exchange was three times
higher than two stage exchange arthroplasty. 121 The lack of
randomized trials, the lack of proven benefit with resistant
Gram-positive and Gram-negative infections, and concerns
over the emergence of resistance with the use of antimicrobiali mpregnated cement during refractory infection' 16 limit the
utility of this surgical approach.
Despite its proven benefit in the treatment of late prosthetic
joint infection, there are situations where exchange arthroplasty
is not feasible and where the quality of life associated with prolonged immobilization is unacceptable to the patient. In these
situations, debridement with retention of the infected prosthesis, followed by indefinite suppressive antibimicrobial
therapy, has been proposed. 122,123 In contrast to prosthesis
retention in the early postoperative period, the goal of therapy
in this situation is not cure but rather indefinite suppression of
infection. Segreti et al reported the utility of this approach in
18 patients with both early and late prosthetic joint infections; 123 eight were infected with Staph. aureus, two with
MRSA, and seven with coagulase-negative staphylococci.
Eleven of the 18 patients (61%) remained successfully suppressed at the end of the study period (median 49 months);
seven discontinued antibiotic therapy, three because of breakthrough infection and four chose voluntarily to stop - relapse
of infection occurred in only one of the four. Other studies have
met with lesser rates of success, ranging from 23 to 63%. 122• 124
Antimicrobial therapy
Staphylococci are the most common infecting organisms and
treatment of these infections is often most challenging. For
strains susceptible to methicillin, nafcillin (oxacillin or flucloxacillin) is the agent of choice; for patients with well-documented allergy to penicillin, vancomycin or clindamycin is
recommended. For staphylococci resistant to methicillin vancomycin is always the drug of choice and should be combined
with rifampicin (rifampin).
Animal models have demonstrated the beneficial impact of
rifampicin-containing antimicrobial regimens in implant-associated infections. 125,126 Growing clinical data confirm these
findings; 105,127 a randomized study conducted by Zimmerli et
al found that administration of a rifampicin-containing regimen
to patients with prosthetic joint infections, who underwent irrigation and debridement with retention of their prosthesis,
resulted in long-term cure in all of the 12 patients who completed at least 3-6 months of therapy. 105 Unless the infecting
organism demonstrates in-vitro resistance or the patient has
known allergy to rifampicin, based on these data we believe
rifampicin should be routinely included in the regimen for all
staphylococcal prosthetic joint infections, especially if vancomycin is used.
Newer fluoroquinolones (other than ciprofloxacin), such as
levofloxacin and gatifloxacin, exhibit excellent in-vitro activity
against staphylococci (although they are often inactive against
MRSA), are highly bioavailable orally, and attain high joint
fluid concentrations in experimental animal models of staphylococcal prosthetic joint infection. 128 Moreover, clinical trials
of oral therapy in chronic osteomyelitis have demonstrated
their equivalency to parenteral regimens, 129,130 although the
studies were underpowered. Fluoroquinolone-containing regi mens for treatment of staphylococcal prosthetic joint infection have shown benefit in a limited number of clinical
studies. 105,127 However, in our opinion the role of fluoroquinolones in the initial antimicrobial regimen for treatment
of prosthetic joint infections caused by staphylococci remains
undefined. Rather, their utility at this time appears to be in the
consolidation phase of therapy, after a patient has completed
a prescribed period of intravenous nafcillin (oxacillin or flucloxacillin) or vancomycin in conjunction with rifampicin; or
for the patient where chronic suppression, rather than cure is
the goal. In-vitro confirmation of susceptibility is necessary
before their use can be considered, and any fluoroquinolonecontaining regimen should also include another effective
antimicrobial, usually rifampicin, as at least one prospective
study has described the emergence of fluoroquinolone resistance during prolonged monotherapy. 105
.82
( CHAPTER 45
I NFECTIONS ASSOCIATED WITH IMPLANTED MEDICAL DEVICES
tive study of 3490 patients with prosthetic joints found that
only seven developed prosthetic joint infection temporally
related to a dental procedure. 69 Five of these seven had underlying co-morbidity that predisposed them to infection, such as
diabetes mellitus or rheumatoid arthritis. Based on these data,
recent recommendations for the use of antibiotic prophylaxis
in patients with prosthetic joints undergoing invasive procedures include patients with rheumatoid arthritis with a prosthesis implanted within the past year, an overt oral infection,
a prolonged dental procedure (>I 15 minutes) and, possibly,
diabetes mellitus or chronic corticosteroid therapy. 145
I NFECTIONS ASSOCIATED WITH
PROSTHETIC HEART VALVES
EPIDEMIOLOGY
Of all complications seen with implanted devices used in
modern medicine, infection of a prosthetic valve is perhaps the
most feared. It is estimated that 60 000 prosthetic valve replacements are performed in the USA each year. 146 Prosthetic valve
endocarditis (PVE) accounts for 10-20% of all cases of endocarditis, 147-149 and the 5-year risk of developing infection of a
prosthetic valve after surgery has remained in the range of 3-6%
since the 1960s. 150-154 The risk of PVE is highest within the first
2-3 months after surgery then falls to approximately 0.1-0.7%
per patient-year thereafter. 150,152,154,155
The risk of infection of mitral and aortic valves appears to
be similar. 150-152,156 However, the risk of infection with mechanical and bioprosthetic valves differs with the proximity to
surgery: mechanical prosthetic valves have a higher incidence
of infection in the first 12 months after implantation 150,151
whereas the incidence of infection after 12 months is higher
with bioprosthetic valves. 150,151 This results in an overall 5-year
risk of infection that is similar for the two types of valves 5.0% for mechanical and 6.3% for bioprosthetic
valves. 150,151,156-158
the endocardium of the annulus and the cloth sewing ring. In
contrast, infection of bioprosthetic valves is more likely to begin
on the valve structure itself. These observations are supported
by older studies showing a much higher rate of perivalvular
abscess with infection of mechanical valves. 110,166 More recent
studies have failed to show such a difference. 15',167,168
As with orthopedic devices, most prosthetic valve infections
are thought to derive from contamination of the valve at the
time of surgery or in the early postoperative period. Similar to
the definitions for early and late infection with orthopedic
devices, infection of a prosthetic valve is arbitrarily defined as
early or late based on whether it manifests within 60 days or
later or, as now promoted by Karchmer, within 12 months of
surgery or later. 168 These arbitrary cutoffs are relevant pathophysiologically because the risk of infection and the organisms
encountered in early and late PVE differ significantly (Table
45.2). Most infecting organisms within the first 12 months
after surgery are common nosocomial pathogens, most notably
Staph. aureus and coagulase-negative staphylococci (Table
45.2); 151 the coagulase-negative staphylococci recovered from
PVE during the first year after surgery are far more likely to be
resistant to methicillin than those recovered more than one
year after surgery (87% versus 22%),168 strongly suggesting
that the former were acquired intraoperatively or in the immediate postoperative period. Furthermore, infections classically associated with native-valve endocarditis, such as
streptococci and the `HACEK' organisms are rarely (if ever)
encountered in PVE until 12 months or longer after valve
implantation (Table 45.2).
Although intraoperative contamination of the valve during
surgery almost certainly accounts for most early postoperative
prosthetic valve infections, 161,170 the contribution of hemato-
Table 45.2 Micro-organisms involved in early and late
prosthetic valve endocarditisa
Outcome with PVE has improved greatly over the past two
decades but mortality remains high and is estimated to range
from 32 to 64%.150,156,159-161 The highest mortality is seen with
early PVE (<_60 days): 92 deaths occurred in a pooled analysis of 180 cases of early PVE (51%). 156,160,162-165 Mortality in
late PVE (>60 days) is lower: 97 deaths occurred in the pooled
analysis of 298 cases of late PVE (32%). 156,160-163
PATHOGENESIS AND MICROBIAL
ETIOLOGY
Late PVEb
( > 12 months)
( n=219)
No. (%)
Coagulase-negative staphylococci
Staphylococcus aureus
Fungi
Gram-negative bacilli
Enterococci
Streptococci
Diphtheroids
HACEKc
Culture-negative
Miscellaneous
98 (37.4)
49 (18.7)
25(9.5)
24(9.1)
23(8.8)
1 2(4.6)
1 0(3.8)
0(0)
1 5(5.7)
6(2.3)
23 (10.5)
41 (18.7)
3(1.4)
11 (5.0)
25 (11.4)
74 (33.8)
5(2.2)
11 (5.0)
17(7.8)
9(4.1)
Pooled data from eight studies of early and late prosthetic valve
endocarditis.15''6'-165,172, 547
b PVE = Prosthetic valve endocarditis.
c HACEK Haemophilus parainfluenzae, Haemophilus aphrophilus,
Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella
corrodens, and Kingella kingae.
a
Infection of newly implanted mechanical and bioprosthetic
valves may begin at the annular sewing line or on the valve
itself. Early studies showed that mechanical valves are relatively resistant to infection of the prosthetic valvular component and that most infections begin at the interface between
Organism
Early PVEb
( 12 months)
( n=262)
No. (%)
I NFECTIONS ASSOCIATED PROSTHETIC HEART VALVES
genous seeding cannot be overlooked. Heavy use of invasive
devices, especially intravascular and urinary catheters, in the
early postoperative period and the risk of nosocomial bloodstream infection related to their use is very high (see
below). 171,172 Studies suggest that 31-92% of cases of early
postoperative PVE stem from another nosocomial infection. 166,168,172 A study by Fang et al further highlights the risk
of PVE in the setting of nosocomial bacteremia: 24% and 10%
of patients with a prosthetic valve exposed to nosocomial
bloodstream infection with Staph. aureus or Gram-negative
bacilli developed secondary PVE, respectively. 171
The organisms causing PVE greatly influence the outcome.
PVE with Staph. aureus and coagulase-negative staphylococci
is associated with a mortality ranging from 28% to
100%156,159-161,163,174-178 and, although data are limited, infections with aerobic Gram-negative bacilli and fungi appear to
be associated with worse outcomes. 171,171 In contrast, mortality from PVE caused by streptococci appears to be much lower,
ranging from 5% to 35%. 161 ,163,165
PVE is not only associated with a higher mortality than that
seen with native valve endocarditis but is also associated with
a higher rate of complications. 111,166-168,180 Infection involving
the suture line results in invasive infection of the annulus and
underlying myocardium, with development of ring abscess,
conduction abnormalities, and dehiscence of the prosthesis
(with valvular incompetence). Moreover, the vegetations on a
mechanical valve can interfere with normal closure, producing regurgitation or, alternatively, functional stenosis. Both
complications are associated with a worse outcome and help
define `complicated PVE':
a new or worsening murmur due to valve dysfunction;
new or worsening congestive heart failure due to valvular
dysfunction or abscess;
new electrocardiographic conduction abnormalities; or
an intracardiac abscess detected by echocardiogram,
surgery, or autopsy. 119,168,178,181
Each of these complications is regarded as a clear-cut indication for surgical replacement of the infected prosthetic valve.
DIAGNOSIS
The clinical presentation of PVE does not differ greatly from
that seen with native valve endocarditis. Signs and symptoms
include fever (>90%), 182 a new or changing murmur
(40-70%), 182 congestive heart failure (30-100%), 182 petechiae
(30-60%), 182 splenomegaly (15-40%), 182 embolic phenomenona, including strokes or transient ischemic attacks
(5-40%), 182 shock (0-30%), 182 and conduction abnormalities
(5-20%). 182 Osler's nodes, Janeway lesions and Roth's spots
are relatively infrequent (5-15%). 182 The likelihood that a
patient will present with one or more clinical signs or symptoms is influenced in greatest measure by the virulence of the
infecting organism. For example, in recent studies, PVE caused
by Staph. aureus was associated with a necrologic event in
I
25-67% of cases, septic shock in 30% of cases and an overall
mortality of 33-75%. 161,163,178
Leukocytosis, anemia and elevations in the ESR and CRP
are common in PVE but are non specific, especially in the early
postoperative period. 182 Isolation of a micro-organism from
blood cultures is usually the first and best clue to PVE, and
obtaining at least two - preferably three - blood cultures before
beginning empiric antimicrobial therapy, is mandatory when
evaluating unexplained fever in a patient with a prosthetic heart
valve. If at least 20-30 ml of blood is obtained from each of
three separate venepuncture sites, 99% of detectable bacteremias should be identified if the patient has not received
recent antimicrobial therapy. 183,184 In rare situations where
blood cultures remain negative despite strong clinical suspicion of PVE, the use of special cultures or serologic tests to
detect fastidious organisms, such as the `HACEK' species,
Legionella spp., rapid growing mycobacteria, Coxiella burneth,
Mycoplasma hominis and fungi other than Candida, should be
employed. 185 The presence of a sustained, high-grade bacteremia or fungemia strongly suggests I'VE and must prompt
further evaluation of the prosthetic valve. 186,187
The availability of transesophageal echocardiography (TEE)
has greatly improved the capacity of clinicians to make a definitive diagnosis of PVE. For a variety of reasons, but most
importantly because of the distance between the transducer
and the heart, transthoracic echocardiography (TTE) can
detect only the largest vegetations on a prosthetic valve in any
location (>10 mm): 188 compared with sensitivity of 17-40%
for TTE189-191 the sensitivity of TEE for the diagnosis of PVE
ranges from 77 to 100%. 165,189,191 Moreover, TEE is greatly
superior to TTE for detection of perivalvular abscess (up to
100% for TEE, 0-40% for TTE) 192,193 and valvular dysfunction (86% .for TEE, 43% for TTE). TEE visualizes the mitral
valve extremely well but may have difficulty visualizing the
entire aortic valve as well as portions of the left ventricular
outflow track, and thus an approach that utilizes both TEE
and TTE is recommended. 194
The combination of clinical signs and symptoms, the results
of blood cultures and echocardiography has been used to formulate criteria for the diagnosis of native valve endocarditis. 195
Application of the Duke criteria to PVE has been evaluated in
several studies; 161,165,178 i n confirmed cases of PVE, Duke criteria for definite PVE were met in 76-79% and criteria for
possible PVE in an additional 20-24% cases. 161,161 PerezVasquez et al have recommended amending these criteria for
the diagnosis of PVE, adding heart failure and conduction disturbances to the minor criteria; 165 adding these two additional criteria increased the percentage of definite cases of PVE
from 79 to 90%, although the effect on specificity was not
addressed.
TREATMENT
The best management of patients with PVE often requires a
combined medical and surgical approach. A careful analysis of
583
B4
I CHAPTE R
45
I NFECTIONS ASSOCIATED WITH IMPLANTED MEDICAL DEVICES
the nature of the infection and the infecting micro-organism
is imperative to determine the best approach. Unfortunately,
even when armed with this information, many aspects of the
care of the patient with PVE remain unclear. For example, the
findings that mandate surgical intervention and the timing of
that intervention are still areas of dispute. Moreover, whether
to continue or discontinue anticoagulation in a patient with an
infected mechanical PVE is also unclear.
Antimicrobial therapy
Antimicrobial therapy must always be withheld until appropriate cultures can be obtained. The decision to then begin
empiric antimicrobial therapy, before the results of cultures are
available, is influenced by the perceived clinical urgency. With
patients who are hemodynamically stable and without signs of
complicated PVE, antimicrobial therapy can generally be safely
withheld until bloodstream infection is confirmed.
With the patient who warrants immediate therapy because
of fulminant sepsis or signs of dehiscence or other complications, therapy should be based on whether he or she has early
PVE (< 12 months after surgery) or late PVE (> 12 months after
surgery) and whether there is infection at a distant focus, such
as urosepsis, surgical site infection, or an infected intravascular
device, that points to a specific organism. Empiric therapy of
patients with PVE should include vancomycin and gentamicin
to cover resistant staphylococci, especially MRSA, enterococci
and enteric Gram-negative bacilli. Antipseudomonal drugs
may be indicated for early PVE in certain clinical settings, such
as ventilator-associated pneumonia with suspected PVE. It is
important to recognize that whereas the use of either vancomycin or gentamicin alone has a low risk of nephrotoxicity or
ototoxicity (1-2%), when these drugs are used in combination
for longer than 3-5 days, especially in elderly patients, the risk
of toxicity rises sharply, to 25% or higher. " 16 Most importantly, the definitive regimen must be based on the identification
and susceptibilities of the infecting organism.
Guidelines for antimicrobial therapy of native and prosthetic
valve endocarditis caused by various organisms are summarized in Table 45.3. In general a bactericidal agent to which
the micro-organism is susceptible should be used; for staphylococci, streptococci and enterococci in combination with gentamicin for at least 2 weeks to enhance the bactericidal activity
of the regimen. 197,198 The duration of therapy for PVE is longer
than for native valve endocarditis, and antibiotic therapy
should generally be continued for a minimum of 6 weeks, often
longer, regardless of whether surgical intervention has occurred
or is planned. Rifampicin may be added to the regimen with
staphylococcal infections, based on its adjunctive value in
osteomyelitis and prosthetic joint infections. 101,125-127
Resistance to rifampicin develops rapidly when it is used as a
single agent or when the microbial burden is high, 126 and it
may be desirable to delay adding rifampicin to the regimen
until after 3-5 days of therapy with other agents. 161 In the presence of high-level aminoglycoside resistance, therapy for enterococcal PVE should be prolonged to 8-12 weeks. The best
therapy for vancomycin-resistant Enterococcus faecium PVE
remains uncertain at this point, although there have been
reports of successful outcomes, both with linezolid 199 and with
quinupristin-dalfopristin. 200
Fungal PVE has been associated with a very poor outcome
and current management mandates surgical replacement of
the infected valve followed by prolonged antifungal
therapy. 179,187 Amphotericin B, with or without 5-fluorocytosine, is recommended for Candida PVE, and some have recommended follow-up long-term suppressive therapy with an
azole, based on reports of recurrent infection after parenteral
therapy has been completed. 179
Surgical therapy
The onset of PVE within 2 months of valve replacement, new
or worsening congestive heart failure due to valve dysfunction,
new high-grade electrocardiographic conduction abnormalities, an intracardiac abscess detected echocardiographically,
infection with staphylococci, Ps. aeruginosa or fungi, uncontrolled infection with persistent bloodstream infection despite
appropriate antimicrobial therapy, relapse of endocarditis after
a full course of appropriate antimicrobial therapy, and fever
that persists beyond 10 days despite appropriate antimicrobial
therapy are all associated with a poor outcome, 198 and are
regarded as indications for surgical intervention, with removal
of the infected prosthetic valve, debridement of the annulus
(and any abscesses found), and implantation of a new prosthetic valve. The decision to intervene surgically must take into
account all of these factors as well as host factors predictive of
poor surgical outcome such as stage IV heart failure, acute
renal failure or, especially, multiorgan failure.
PVE presenting with severe heart failure, while associated
with high operative mortality, is almost universally fatal within
6 months without surgery."" Studies have shown that patients
with paravalvular abscesses, which occur in 45-60% of patients
with PVE, 150,166 have survival rates approaching 80% when a
combined medical-surgical approach is employed. 2 ° 1,202 In a
recent study, Staph. aureus PVE treated medically was associated with a mortality of 83% whereas treatment with a combined medical-surgical approach was associated with a 20%
mortality, 1 's a difference that remained highly significant, even
after correcting for age, severity of illness and medical comorbidities.
Ideally, patients with clear indications for surgery but risk
factors for a poor outcome should be taken immediately to the
operating room before their heart failure worsens or their renal
function is compromised - but, understandably, surgeons may
be hesitant to perform valve replacement, which is associated
with a mortality of 10-30% in experienced hands, 201,202 when
patients appear to be clinically stable and seem to be responding to antimicrobial therapy. Moreover, there is obviously
theoretical concern about reimplanting a new prosthetic valve
in an infected surgical site; however, the data indicate that the
rate of recurrent PVE is low, 6-15%. 159,202,203 Finally, delaying
surgery to provide a longer duration of antimicrobial therapy
586
I CHAPTER 45
I NFECTIONS ASSOCIATED WITH IMPLANTED MEDICAL DEVICES
in the hopes of sterilizing the surgical bed has not been shown
to improve outcome. 2 °2 Thus, the data indicate that a patient
presenting with one or more indications listed in Table 45.6
will benefit from early cardiac surgery.
Anticoagulation
A final controversial aspect of the care of patients with PVE is
the decision whether to continue anticoagulation. Currently,
most patients with bioprosthetic heart valves are anticoagulated
for the first 3 months after valve replacement; 2° 4 however, in
the setting of bioprosthetic valve endocarditis, the risk of anticoagulation outweighs the benefit and oral anticoagulants
should be discontinued.
In contrast, patients with mechanical prosthetic heart valves
have an annual risk of embolic stroke that approaches 4%
without anticoagulation,2°s and discontinuing anticoagulation
in these patients is more problematic. Anticoagulation of
patients with infected mechanical valves appears to offer protection against embolic stroke: in a large cohort study, patients
with mechanical PVE who were anticoagulated had a much
lower risk of stroke than patients who were not receiving anticoagulants (12% versus 42%).206
Unfortunately, when stroke occurs in anticoagulated
patients there is a higher risk of hemorrhagic extension, 161,178,207
especially if Staph. aureus is the infecting pathogen. Studies
suggest that the risk of neurologic deterioration is increased
when patients with an embolic stroke undergo cardiac surgery
within 2-3 weeks of the event, presumably because of the need
for heparinization during cardiopulmonary bypass. 2°$ Thus, it
is generally considered desirable to continue anticoagulants in
patients with mechanical valves and PVE, but every effort must
be made to avert excessive anticoagulation; using intravenous
heparin may provide a safer alternative during the early phase
of therapy. Finally, if cerebral embolism does occur, anticoagulation should be withheld for several days to reduce the risk
of hemorrhagic complications, and surgical intervention should
be delayed, if possible, for at least 2-3 weeks to allow stabilization of the cerebral vasculature. 2 os
PREVENTION
Prosthetic heart valves, whether bioprosthetic or mechanical,
are considered at high risk for endocarditis in the latest
American Heart Association guideline, 2°9 and the use of prophylactic antibiotics before procedures that are likely to
produce bacteremia is recommended to prevent late PVE.
Interventions that reduce the risk of intraoperative contamination at the time of surgery will have the greatest impact on
prevention of early PVE. 21 ° ,211 Therefore, scrupulous asepsis
and meticulous surgical technique combined with perioperative antimicrobial prophylaxis with drugs exhibiting antistaphylococcal activity - cefazolin, cefuroxime or cefamandole
- forms the cornerstone of prevention of PVE. Vancomycin
should not be routinely used for prophylaxis unless the hospi-
tal has a high rate of MRSA infection or the patient is a known
MRSA carrier. 21 o,212
A novel silver-coated St. Jude valve (Silzone®, St. Jude
Medical Inc.) has been advocated to prevent recurrent PVE,
with anecdotal success. The large, multicenter, Artificial Valve
Endocarditis Reduction Trial (AVERT) trial was undertaken
in 1999 213 with the goal of assessing the efficacy of the novel
medicated valve; however, there have been reports of recurrent PVE despite its use. 214 Most importantly, enrollment in
the AVERT trial was suspended in January 2001 because of
evidence of increased paravalvular incompetence in patients
who received the silver-coated valve.
PACEMAKER INFECTIONS
EPIDEMIOLOGY
Approximately 370 000 pacemakers were implanted in the
USA in 1996. 39 Pacemaker infection manifests clinically in one
of three ways depending on the type of pacing leads used:
localized infection of the pulse generator pocket;
pericarditis and/or mediastinitis due to infection of epicardial pacing leads; or
primary bloodstream infection in association with rightsided
endocarditis due to infection of transvenous endocardial
pacing leads.
Overall rates of infection following implantation of a permanent pacemaker range from 1 to 7%.215-219
Pacemaker endocarditis, a complication seen almost exclusively with endocardial pacing leads and caused mainly by
Staph. aureus, occurs least commonly (0.5-1% of implantations).21 '.22 °> 221 However, mortality is high, approaching 40%
without removal of the infected leads. 217,220
Infection of the pulse-generator pocket is far more common
in the early post-implant period, but can occur years later when
the pacemaker battery is replaced. 216 Invasive infection of the
pacing leads typically manifests late, although infection may
develop early if the leads become contaminated at the time of
implantation.
The risk of pacemaker infection is increased in patients with
diabetes mellitus or underlying malignancy, 217 . 222 with operator inexperience, 222,223 with manipulation of the pacemaker
such as replacement of the battery, 216 and if the patient requires
a temporary transvenous pacemaker before implantation of the
permanent pacemaker. 222
PATHOGENESIS
Infection occurs early (< 2 weeks), intermediate (2 weeks to 6
months), or late in the post-implantation period (> 6 months).
Infections of the pulse-generator pocket constitute the majority of early and intermediate pacemaker infections, deriving
PACEMAKER INFECTIONS
from contamination of the pulse generator pocket by cutaneous
organisms at the time of implantation . 224 Seeding of epicardial
leads also occurs most frequently at the time of implantation,
less often later, by migration of infection from the pulsegenerator pocket, and thus also tends to present in the early
and intermediate post-implantation period. Infection of transvenous pacemaker leads may occur at implantation, 217 with
migration of micro-organisms from an infected pulse-generator
pocket, or derive from hematogenous seeding during a late
bloodstream infection, 225,226 and these infections tend to
present in the intermediate or late post-implantation period,
few presenting early.
I
bloodstream infection that typically does not quickly clear after
starting antimicrobial therapy. Therefore, patients with endocardial pacing lead infection, in addition to manifesting signs
of right-sided endocarditis, usually show high-grade bloodstream infection, despite days of appropriate antimicrobial
therapy. 195,221 Echocardiography shows vegetations on the
endocardial leads and/or the tricuspid valve, and is valuable
for confirming infection. TEE, with a sensitivity that ranges
from 91 to 96% (compared with a 22-43%. sensitivity seen
with TTE) is preferred. 217,225,226,232
TREATMENT
MICROBIOLOGY
Predictably, most pacemaker infections are caused by Grampositive organisms, especially Staph. aureus or coagulase
negative staphylococci. 222,226,227 Propionibacterium acnes,
Gram-negative bacilli and Candida albicans account for most
of the rest. Rare cases of late pacemaker endocarditis caused
by viridans streptococci or enterococci have been reported. 221
Finally, rare organisms implicated in pacemaker infection have
included Brucella melitensis, 22s non-tuberculosis mycobacteria, 229 Aspergillus Spp.23° and Petriellidium boydii. 231
DIAGNOSIS
The clinical presentation of pacemaker infection depends on
whether it involves the pulse-generator pocket or the pacing
leads. Infection of the pulse-generator pocket typically occurs
shortly following implantation or battery exchange, and manifests with localized erythema, pain, and fluctuance, occasionally with erosion of the overlying skin. Rarely, migration of
infection from the pocket produces pericardial involvement
(when epicardial leads are used) or bloodstream infection, with
endocardial leads. Infection of endocardial pacing leads typically presents as a primary bloodstream infection that varies in
severity, depending on the causative organism: indolent febrile
illness with coagulase-negative streptococci as contrasted with
fulminant sepsis with Staph. aureus. In either case, signs and
symptoms of right-sided endocarditis are often present, including fever and chills (> 80%), 225.226 septic pulmonary emboli
(20-45%), 225,226 and tricuspid regurgitation (25%). 225,226
A presumptive diagnosis of a pulse-generator pocket infection can usually be made on clinical grounds alone and is confirmed by a percutaneous aspirate from the pocket that shows
micro-organisms on Gram stain or in culture. Diagnosing
infection of an epicardial pacing lead can be more challenging
unless bloodstream infection is present. Cryptogenic pericarditis or mediastinitis are usually identifiable by computed
tomography (CT) or magnetic resonance imaging (MRI) of
the chest but microbiologic confirmation is mandatory if blood
cultures are non-diagnostic. As seen with PVE, foreign bodyrelated endovascular infections are associated with high-grade
Successful treatment of pacemaker-related infection usually
requires a combined medical and surgical approach. While
isolated reports have claimed successful eradication of pacemaker infections with limited debridement followed by prolonged antimicrobial therapy, most of the published series
report an unacceptably high failure rate unless the entire pacing
system, including the battery pack and pacing wires, is
removed. 218,225-227,233,'34 Lewis et al found that 31 of 32
patients with pacemaker infection treated at their center with
medical therapy alone recurred and ultimately required
removal of the entire pacing system to achieve cure. 227 Similar
experiences were reported by Molina et al, who found that 12
of 12 patients treated medically suffered recurrence. 233 Most
importantly, the mortality with infected endocardial leads is
greatly increased in patients treated medically, as shown in an
analysis of 182 cases by Cacoub et al, who found a 41% mortality in medically treated patients, compared with 18% in
patients whose entire pacemaker was removed. 226
Traditional management mandates removal of the entire
infected pacing system, placement of a temporary pacemaker,
if indicated (not indicated in 13-52% of patients 235 ), followed
by several weeks of parenteral antibiotic therapy, after which
a new battery and endocardial pacing system are implanted.
Recent studies have shown low recurrence rates with removal
of the entire infected pacemaker followed by immediate placement of a new permanent epicardial pacing system, obviating
the need for temporary pacing. 236
Transcutaneous extraction of infected endocardial leads that
have been in place for prolonged periods is often difficult, as
the lead is incorporated into a fibrous sheath in the right atrium
and traction fails to dislodge the infected lead in 14-36% of
cases. 235,237 In this situation, open-heart surgical extraction is
usually necessary. Recently, a transvenous excimer laser
sheath237,23 e has permitted successful lead extraction in 94%
of cases, as contrasted with only 64% in a group where simple
traction and a telescoping sheath were utilized. 237
Removal of an infected lead with large vegetations by transcutaneous extraction engenders concern over potential
embolization. A study by Klug et al demonstrated that 30% of
patients with endocardial lead vegetations had scintigraphic
evidence of pulmonary emboli following removal of the lead, 22 s
although none of these patients developed clinical symptoms.
587
88
1 CHAPTER 45
I N FECTIONS ASSO CIATED WIT H I MPLANTED MEDICAL DEVICES
Several series have reported successful transcutaneous extraction of infected leads with vegetations > 10 mm in size; 232,239
however, concerns remain with vegetations this size and some
authorities recommend proceeding directly to surgical
removal. 240
appreciated potential for producing iatrogegic disease, particularly bloodstream infection originating from infection of the
percutaneous device used for vascular access or from contamination of the infusate administered through the device. 243
More than one-half of all epidemics of nosocomial bacteremia
or candidemia derive from vascular access in some form. 244,245
More than 250 000 intravascular device (IVD) related
bloodstream infections occur in the USA each year, 246 each
associated with 12-25% attributable mortality, 243,247-249 prolongation of hospital stay, 243,248-251 and an added cost to healthcare of $33 000-$35 000.243,248,250,251
Prospective studies in which every IVD was cultured at the
time of removal show that every device carries some risk of
causing bloodstream infection, but the magnitude of risk varies
greatly (Table 45.4) . 212
PREVENTION
Strict aseptic technique and well-trained, experienced operators are be associated with reduced rates of pacemaker-related
infection. 223 Antibiotic prophylaxis has traditionally been discouraged, except in high-risk patients, 241 however, a recent
meta-analysis that encompassed 2023 patients found that
routine antibiotic prophylaxis with anti-staphylococcal drugs
was associated with a 75% reduction in pacemaker-related
infections (CI 0.10-0.66, p = 0.005). 242 Unfortunately, heterogeneity of the studies and inclusion of only a single, doubleblinded, randomized trial limits application of this analysis. If
prophylaxis is to be used, an antistaphylococcal drug, such as
cefuroxime or cefazolin, is recommended (vancomycin if the
patient has been colonized by or has had previous infection
with MRSA).
PATHOGENESIS
There are two major sources of IVD-related bloodstream infection:
1. Colonization of the IVD; catheter-related infection.
2. Contamination of the fluid administered through the device;
infusate-related infection. 253
I NFECTIONS RELATED TO
I NTRAVASCULAR DEVICES
Contaminated infusate is the cause of most epidemic IVDrelated infections and has been reviewed elsewhere. 246 In contrast, catheter-related infections are responsible for most
endemic infections and comprise the focus of this review.
In order for micro-organisms to cause IVD-related infection they must first gain access to the extraluminal or intraluminal surface of the device, where they can adhere and
become incorporated into a biofilm that allows sustained infection and hematogenous dissemination. 254 Micro-organisms
gain access by one of three mechanisms (Figure 45.2): (1) skin
organisms invade the percutaneous tract, probably facilitated
EPIDEMIOLOGY
Reliable vascular access for administration of fluids and electrolytes, blood products, drugs, nutritional support and for
hemodynamic monitoring has become one of the most essential features of modern medical care. Unfortunately, vascular
access is associated with substantial and generally under-
Table 45.4 Rates of intravascular device-related bloodstream infection associated with the major types of devices used in
clinical practices
Rates of infection
per 100 devices
Type of intravascular device (no. studies)
per 1000 device days
Pooled mean
95% CI
Pooled mean
95% CI
Peripheral venous catheters (13)
0.2
0.1-0.3
0.6
0.3-1.2
Arterial catheters used for hemodynamic monitoring (6)
1.5
0.9-2.4
2.9
1.8-4.5
Short-term, non-cuffed, non-medicated central venous
catheters (61)
3.3
3.3-4.0
2.3
2.0-2.4
Pulmonary artery catheters (12)
1.9
1.1-2.5
5.5
3.2-12.4
1 6.2
1 3.5-18.3
2.8
2.3-3.1
6.3
4.2-9.2
1.1
0.7-1.6
1.2
0.5-2.2
0.4
0.2-0.7
20.9
1 8.2-21.9
1.2
1.0-1.3
5.1
4.0-6.3
0.2
0.1-0.2
Hemodialysis catheters
Non-cuffed (15)
Cuffed (5)
Peripherally inserted central catheters (8)
Long-term tunneled and cuffed central venous catheters (18)
Subcutaneous central venous ports (13)
a
Based on 206 published prospective studies in which every device was evaluated for infection; Kluger and Maki, 2001? 52
I NFECTIONS RELATED TO INTRAVASCULAR DEVICES (
Skin organisms
Endogenous flora
Extrinsic (HCW)*
Contaminated disinfectant
I nvading wound
Contamination
of
catheter hub
Extrinsic (HCW)*
Endogenous (skin)
Contaminated
i nfusate
Fluid
medication
Extrinsic
( manufacturer)
Contamination of device
prior to insertion
Extrinsic >> manufacturer
Skin
Hematogenous
From distant local infection
*HCW: health care worker
Fig. 45.2 Routes of microbial colonization in the pathogenesis of intravascular devicerelated bloodstream infection (adapted from Maki and Mermel,1998 246).
by capillary action25 s at the time of insertion or in the days following; (2) micro-organisms contaminate the..catheter hub
(and lumen) when the catheter is inserted over a percutaneous
guidewire or later manipulated; 56 or (3) organisms are carried
hematogenously to the implanted IVD from remote sources of
local infection, such as a pneumonia. 244,217
With short-term IVDs (in place <10 days) - peripheral
intravenous catheters, arterial catheters and non-cuffed, nontunneled central venous catheters - most device-related bloodstream infections are of cutaneous origin, from the insertion
site, and gain access extraluminally, occasionally intraluminally. 258,259
In contrast, contamination of the catheter hub and lumen
appears to be the predominant mode of infection with longterm, permanent IVDs (in place >10 days), such as cuffed
Coagulase-negative
staphylococci
Staphylococcus
aureus
Enteric gram-negative
bacilli
Pseudomonas
aeruginosa
Hickman- and Broviac-type catheters, cuffed hemodialysis
central venous catheters (CVCs), subcutaneous central ports
and peripherally inserted central catheters. 260-262
MICROBIOLOGY
Micro-organisms found on patients' skin and which gain access
to the IVD extraluminally, occasionally intraluminally - coagulase-negative staphylococci (39%), Staph. aureus (26%), and
Candida species (11%) - account for 76% of IVD-related
infections with short-term, non-cuffed devices of all types; only
14% are caused by Gram-negative bacilli (Figure 45.3). 263 In
contrast, with long-term surgically implanted devices such as
cuffed and tunneled catheters, peripherally inserted central
8%
Corynebacterium spp.
Enterococci
Miscellaneous
Fig. 45.3 Microbial profile of intravascular device-related bloodstream infection based
on an analysis 159 published prospective studies? 63
589
90
I CHAPTER 45
I NFECTIONS ASSOCIATED WITH IMPLANTED MEDICAL DEVICES
catheters and subcutaneous central venous ports, coagulasenegative staphylococci (25%) and Gram-negative bacilli (45%)
(which most commonly gain access intraluminally and contaminate infusate in the device) account for 76% of IVD-related
bloodstream infections; only 2% are caused by Candida species
(Figure 45.3) . 213
DIAGNOSIS
Despite the challenge in identifying the source of a patient's
signs of sepsis, 264 several clinical, epidemiological, and microbiologic findings point strongly towards an IVD as the source
of a septic episode. 246 Patients with the abrupt onset of signs
and symptoms of sepsis without any other identifiable source
should prompt suspicion of infection of an IVD. 246 The presence of inflammation, with or without purulence, at the IVD
insertion site, while present in the minority of cases, when combined with signs and symptoms of sepsis has been shown to be
predictive of IVD-related bacteremia and should prompt
removal of the IVD. 246 Finally, recovery of certain microorganisms in multiple blood cultures, such as staphylococci,
Corynebacterium or Bacillus spp., or Candida or Malassezia spp.,
strongly suggests infection of the IVD.
Removal and culture of the IVD has historically been the
gold standard for the diagnosis of IVD-related infections, particularly with short-term catheters. Numerous studies have
demonstrated the superiority of semiquantitative or quantitative culture methods over qualitative broth culture for the diagnosis of such infections. 265,266 Growth of >>-15 cfu from an IVD
segment by semiquantitative culture or growth of ?103 cfu
from a catheter segment cultured after sonication, when
accompanied by local signs of infection or the systemic inflammatory response syndrome (SIRS) usually indicates infection
of the IVD. The diagnosis of IVD-related bloodstream infection is completed when a heavily colonized IVD is associated
with concurrent infection, with no other plausible source (i.e.
primary bloodstream infection); the linkage becomes virtually
certain when the strains recovered from the colonized IVD and
from blood cultures are shown to be identical by phenotypic
or, better, genotypic subtyping. 267-269
Semiquantitative and quantitative cultures of IVDs obviously require their removal. As noted, this can be a major
problem in patients with long-term, surgically implanted IVDs
such as Hickman and Broviac catheters, cuffed and tunneled
hemodialysis catheters and subcutaneous central venous ports.
Prospective studies of patients with long-term IVDs have
shown that only 25-45% of episodes of sepsis represent true
IVD-related bloodstream infection. 270,271 Thus, it would seem
that development of in-situ methods of detecting such infections that do not require removal of the IVD would be of great
utility to clinicians and patients, and in research studies.
If a laboratory is prepared to do pour-plate blood cultures
or has available an automated quantitative system for culturing blood, such as the Isolator® lysis centrifugation system
( Wampole Laboratories, Cranbury, NJ), quantitative blood
cultures drawn through the IVD and concomitantly by
venepuncture from a peripheral vein (or another IVD) can
permit the diagnosis of IVD-related bacteremia or fungemia
to be made with sensitivity and specificity in the range of
80-95%, 266 without removal of the catheter, if empiric antimicrobial therapy has not yet been initiated. With infected
IUDs, the blood culture drawn through the device usually
shows a five- to ten-fold rise in the concentration of organisms
compared to the quantitative blood culture drawn percutaneously from a peripheral site. High grade peripheral candidemia (?25 cfu/ml) reflects an infected IVD 90% of the
time.' 86 Quantitative IVD-drawn blood cultures are most
useful for the diagnosis of infection with long-term devices but,
because of their expense, have had limited utility for the diagnosis of infections associated with short-term devices.272 There
is evidence that a single quantitative culture drawn from a longterm device, even without an accompanying quantitative
culture drawn from the periphery, can accurately identify IVDrelated infection if there is >100 cfu/ml of growth. 266
Quantitative blood cultures are labor intensive and cost
almost twice as much as standard blood cultures. 266 The wide
availability of radiometric blood culture systems (e.g.
BACTEC system®, Becton Dickenson), in which blood cultures are continuously monitored for microbial growth
(approximately every 20 min), has led to a clever application
of this system for the detection of IVD-related bloodstream
infection. The differential-time-to-positivity of blood cultures
drawn through the IVD and concomitantly from a peripheral
site has been evaluated as a surrogate for paired quantitative
blood cultures. Detection of positivity in a blood culture drawn
from the IVD more than 2 h before positivity of the culture
drawn from a peripheral site has been shown to be highly predictive of IVD-related infection, in one study correctly identifying 16 of 17 such infections with long-term catheters, yielding
an overall sensitivity of 94% and specificity of 91%. 273
Subsequent studies with short-term catheters, used mainly in
the intensive care unit (ICU), have generally found lower predictive values, 274 probably related to the extraluminal pathogenesis of infection with most of these devices.
Another simple but rapid and potentially cost-effective
method of detecting IVD-related infection is acridine-orange
leukocyte cytospin (AOLC) staining, combined with Gram
staining, of a sample of lysed and centrifuged blood drawn
from the suspected IVD. In a recent prospective study of 124
adult surgical patients, this method was found to be 96% sensitive and 92% specific. 275 In contrast, AOLC with Gram staining was found in a recent prospective study to be of limited
utility in diagnosing infection with short-term IVDs (mean
duration of catheterization 6 days): AOLC failed to diagnose
all 12 confirmed IVD-related infections. Therefore, AOLC
with Gram stain will probably remain useful primarily for diagnosing infections associated with long-term IVDs. 27 °
In-situ testing using a novel culture-brush, which can be
passed down the lumen and out the end of a long-term IVD
to pick up luminal biofilm and colonized fibrin and thrombus
around the tip, has also been proposed as an alternative to
I NFECTIONS RELATED TO INTRAVASCULAR DEVICES
removal and culture of the IVD. A prospective study that compared use of the endoluminal brush with semiquantitative
culture of removed IVDs found the brush to be 95% sensitive
and 84% specific. 276 However, a subsequent study failed to
demonstrate this level of efficacy: van Heerdan et al found that
use of the endoluminal brush was associated with a sensitivity
of 21% although the specificity was 100%. 2" The predominance of organisms on the extraluminal surface of infected
short-term catheters may limit the utility of the brush-culture
in the ICU.
TREATMENT
If a short-term vascular catheter is suspected of being infected because the patient has no obvious other source of infection to explain fever, there is inflammation at the insertion site,
or cryptogenic staphylococcal bacteremia or candidemia has
been documented, blood cultures should be obtained and the
catheter should be removed and cultured. Failure to remove
an infected catheter puts the patient at risk of developing septic
thrombophlebitis with peripheral intravenous catheters, septic
thrombosis of a great central vein with central venous
catheters,278 or even endocarditis. Continued access, if necessary, can be established with a new catheter inserted in a new
site. A new catheter should never be placed in an old site over
a guidewire if the first catheter is suspected of being infected,
especially if there is purulence at the site.
Bloodstream infection that might have originated from a
cuffed and tunneled central venous catheter does not automatically mandate removal of the device, unless:
there has been persistent exit site infection,
the tunnel is obviously infected,
there is evidence of complicating endocarditis, septic
thrombosis, or septic pulmonary emboli, the infecting
pathogen is Staph. aureus, 219 Corynebacterium jeikeium, 28° a
Bacillus species, 281 Stenotrophomonas spp., Burkholdena
cepacia and all pseudomonal species,282 a filamentous fungus
or Malassezia species,283 or a mycobacterial species; 284
bacteremia or candidemia persists for more than 3 days
despite adequate therapy.
Studies of 7-21 days of antibiotics infused through the
infected line have shown success rates of 60-91% without
catheter remova1, 285-287 although there was significant variability in the response rates depending on the infecting microorganism; with infections due to coagulase-negative
staphylococci, the risk of recurrent bacteremia has been
approximately 20%. 288 Several studies have reported successful treatment of IVD-related infections due to Candida spp.
without removing the device by administering prolonged
courses of amphotericin B administered through the
catheter;289,29o however, this is in contrast to the results of other
prospective studies that found an increased duration of candidemia and mortality in patients who retained their infected
IVD. 291,292
I
In addition to infusion of systemic antibiotics through the
infected line, which is mandatory for any patient with documented IVD-related infection, instillation of a highly concentrated solution of the antibiotic or antibiotic combination,
`locked' into the infected tunneled catheter, may be of adjunctive value to `cure' an infected long-term IVD. In-vitro testing
has proven the long-term stability of solutions of most antimicrobial agents over periods of time as long as 10 days. 293
In small, uncontrolled clinical trials, `antibiotic lock
therapy', usually in conjunction with systemic antibiotic
therapy, has shown `cure' rates with infected IVDs in excess
of 90%294' 295 but the vast majority of IVDs reported in these
studies were infected with Gram-positive organisms other than
Staph. aureus or Bacillus spp. (primarily coagulase-negative
staphylococci or Gram-negative bacilli other than Ps. aeruginosa). Data are lacking on the value of lock therapy for IVDrelated fungemia, and therefore at this time it cannot be
recommended for the management of long term IVDs infected by Staph. aureus, Bacillus spp., Corynebacterium jeikeium,
Stenotrophomonas spp., Burk. cepacia, all pseudomonas species,
fungi or mycobacterial species.
Historically, central ports are rarely curable with medical
therapy alone if the device is clearly infected (e.g. an aspirate
from the port shows heavy growth). 296,297 In-vitro studies of
antibiotic lock solutions in simulated models of infected central
ports raise the possibility of using antibiotic lock therapy to preserve these long-term devices when they become infected. A
recent study of patients with AIDS with central ports who
developed IVD-related bloodstream infection found that lock
therapy combined with systemic antibiotic therapy resulted in
70% of the ports being salvaged (although long-term follow-up
was not reported). A recent larger clinical trial of antibiotic lock
therapy for central port infections achieved salvage rates less
than 50%. 298 Based on the marginal efficacy of the technique
in these two studies and the historically poor cure rate achieved
with systemic antibiotics alone, we believe that definitive treatment of infected central ports mandates their removal.
The decision to treat a suspected IVD-related infection
before microbiologic confirmation (i.e. empirically) comes
down to clinical judgment, weighing the evidence suggesting
bloodstream infection and the risks of delaying treatment. In
general, fever or other signs of sepsis in a granulocytopenic
patient must be regarded as infection until proven otherwise.
If IVD-related bloodstream infection is suspected after cultures have been obtained, the combination of intravenous vancomycin (for staphylococci resistant to methicillin) with a
fluoroquinolone (preferably ciprofloxacin) or with cefepime or
a carbapenem (for aerobic Gram-negative bacilli) should prove
effective against the bacterial pathogens most likely to be
encountered. Initial therapy can then be modified based on the
microbiologic identity and susceptibility of the infecting organisms.
While there are no prospective data to guide the duration
of antimicrobial therapy for IVD-related infections, most coagulase-negative staphylococci infections can be cured with 5-7
days of therapy246,288,299,30 o whereas most infections caused by
591
592
I CHAPTER 45
I NFECTIONS ASSOCIATED WITH IMPLANTED MEDICAL DEVICES
other micro-organisms can be adequately treated with 10-14
days of antimicrobial therapy. 299-301 These recommendations
hold only as long as there are no complications related to the
infection - endocarditis, septic thrombophlebitis, septic thrombosis, or metastatic infection such as osteomyelitis - and the
infection clears within 72 h of initiating therapy. Nosocomial
enterococcal bacteremia deriving from an IVD is rarely associated with persistent endovascular infection, and unless there
is clinical or echocardiographic evidence of endocarditis, treatment with intravenous ampicillin or vancomycin alone for 7-14
days should suffice. 302
The management of Staph. aureus device-related infection
deserves special mention, as there have been no prospective
studies to evaluate the optimal duration of therapy for such
infection. Historically, high rates of associated infectious endocarditis and late complications led to a universal policy of 4-6
weeks of antimicrobial therapy for all patients with Staph.
aureus bacteremia. Earlier diagnosis and initiation of bactericidal therapy of nosocomial Staph. aureus bacteremias in recent
years have been associated with lower rates of infectious endocarditis and metastatic complications, prompting suggestions
that short-course therapy (14 days) is effective and safe for
most cases of IVD-related Staph. aureus bacteremia if the
patient defervesces within 72 h and there is no evidence of
metastatic infection. 303,304 In a study where TEE was routinely
performed in 103 hospital patients with Staph. aureus bacteremia, 69 related to an IVD, Fowler et al found a surprisingly high rate of late complications, 23% with IVD-related
Staph. aureus bacteremia. 305 More recently, these authors
reported that TEE is a cost-effective way to stratify patients
with IVD-related Staph. aureus infection into short-course or
long-course regimens. However, at this time there are no
prospective studies to confirm this approach. Until more data
are available, short-course antimicrobial therapy for IVDrelated Staph. aureus bacteremia therapy should be used only
when TEE is unequivocally negative, the patient has defervesced within 72 h of starting therapy, and there is no evidence
of distant metastatic infection.
All patients with IVD-related candidemia should be treated,
even if the patient becomes afebrile and blood cultures spontaneously revert to negative following removal of the IVD
without antifungal therapy. 306,307 IVD-related candidemia that
responds rapidly to removal of the catheter and institution of
intravenous amphotericin B can be reliably treated with a daily
dose of 0.3-0.5 mg/kg and a total dose of 3-5 mg/kg. 306,307
Fluconazole (400 mg/day) has been shown to be as effective
as amphotericin B in randomized trials in non-neutropenic
patients,308 and has further been shown to be comparable to
amphotericin B in observational studies of neutropenic patients
with Candida IVD-related infection 309 but should not be used
with infections associated with septic thrombosis and highgrade candidemia or, obviously, with infections caused by fluconazole-resistant organisms such as Candida krusei or Candida
glabrata.
All patients with an IVD-related bloodstream infection must
be monitored closely, for at least 6 weeks after completing
therapy, especially if they have had high-grade bacteremia or
candidemia, to detect late-appearing endocarditis, 278,306
retinitis306 or other metastatic infections, such as vertebral
osteomyelitis. 310
PREVENTION
Over the past decade many investigators have evaluated strategies for the prevention of IVD-related infections, with greater
success than with any other form of nosocomial infection. 246,311,312 Guidelines for the prevention of such infections
were last issued by the Hospital Infection Control Practices
Advisory Committee in 1996 and have recently been revised. 313
Wide adoption of these measures has resulted in a substantial
decline in hospital-acquired primary bloodstream infections in
centers in the USA. 314 More consistent application of control
measures and wider acceptance of novel technologies shown
to be effective (and cost-effective) will be needed to reduce this
rate further.
Aseptic technique
Although there has been considerable controversy as to the
level of barrier precautions necessary during insertion of a
CVC, recent studies259,31 s have shown that the use of maximal
barriers - a long-sleeved, sterile surgical gown, mask, cap and
large sterile drape, sterile gloves - significantly reduces the risk
of CVC-related infection. The use of maximal barriers has
further been shown to be highly cost-effective. 315 Such measures are not necessary, however, for peripheral venous or arterial catheters used for hemodynamic monitoring, where sterile
gloves and a small sterile fenestrated drape will suffice.
Given the evidence for the importance of cutaneous microorganisms in the genesis of IVD-related infection, the choice
of the chemical antiseptic for disinfection of the insertion site
would seem of high priority. In the USA, iodophors such as
10% povidone-iodine are widely used. Eight randomized,
prospective trials have compared a chlorhexidine-containing
antiseptic with povidone-iodine for disinfection of the skin
before insertion of IVDs: both agents were well tolerated in
every trial, seven of eight found lower rates of catheter colonization, and three showed a significant reduction in CVCrelated infections in the chlorhexidine-containing antiseptic
group. 316-318 These studies indicate that chlorhexidine is superior to iodophors and should be the antiseptic of first choice
for vascular access. 313
Novel dressings
IVDRs can be dressed with sterile gauze and tape or with a
sterile transparent, semipermeable, polyurethane film dressing. The available data suggest that the two types of dressings
are equivalent in terms of their impact on IVD-related infectlons. 267,319-321
Based on the superiority of chlorhexidine for cutaneous dis-
I NFECTIONS RELATED TO INTRAVASCULAR DEVICES
infection of vascular access sites, a novel chlorhexidine-impregnated sponge dressing has been developed (Biopatch®, Johnson
and Johnson Medical Inc.) and evaluated in three trials to
date.322-324 A large prospective, randomized trial comparing
the use of the chlorhexidine dressing to a standard
polyurethane dressing with short-term central venous and arterial catheters in adults admitted to two teaching hospital ICUs
showed a 60% reduction in catheter-related bloodstream infections with use of the chlorhexidine sponge dressing (adjusted
RR 0.38, p = 0.01), with no adverse reactions associated with
its use. 324 Moreover, testing of the in-vitro susceptibility of isolates from infected catheters in both groups showed no evidence that the antiseptic dressing promoted resistance to
chlorhexidine.
Innovative IVD design
Hickman and Broviac catheters incorporate a subcutaneous
Dacron" cuff which becomes ingrown by host tissue, creating
a mechanical barrier against invasion of the tract by skin organisms. Rates of bloodstream infection per 1000 days with these
catheters are far lower than with short-term percutaneously
inserted, non-cuffed CVCs inserted in the ICU (Table
45.4).246,252 and can be considered a quantum advance for safer
long-term vascular access.
Surgically implanted subcutaneous central venous ports,
which can be accessed intermittently with a steel needle, have
been associated with the lowest rates of bloodstream infection
(Table 45.4; p. 588). A prospective observational study of
Hickman catheters and central ports in oncology patients
showed that for patients needing intermittent central access,
ports appear to carry lower risk of IVD-related infection. 290
Studies also suggest that peripherally inserted central
catheters pose substantially lower risks of infection than standard non-tunneled, non-cuffed CVCs (Table 45.4),252 perhaps
because bacterial colonization on the arm is lower than the
neck or upper chest . 262
A novel CVC made of polyurethane that is impregnated
with minute quantities of silver sulfadiazine and chlorhexidine
(ArrowGard®, Arrow International) became available approxi mately 10 years ago. There have now been 15 randomized
trials of this catheter for prevention of related infection. Most
have demonstrated a reduction in colonization of the catheter
but only two studies were able to show a significant reduction
in CVC related bloodstream infections. 26 s,325 I n the most rigorous study to date 268 which used molecular subtyping to conclusively identify CVC-related infections, the antiseptic
catheter was associated with a two-fold reduction in catheter
colonization and a five-fold reduction in catheter-related bloodstream infection (RR 0.21, p = 0.03). In-vitro analysis of 58
isolates from infected catheters in the two groups showed no
evidence that use of the antiseptic catheter induced resistance
to chlorhexidine and silver sulfadiazine. Use of the antiseptic
catheter was shown to be highly cost effective if baseline rates
of catheter-related blood infection exceeded 2% (3.3 per 1000
IVD-days).
I
Recent meta-analyses by Veenstra et a1 326 and Merme1311
have shown that chlorhexidine-silver sulfadiazine-impregnated
CVCs reduce rates of catheter related infection by at least 40%
(OR 0.40-0.56). Veenstra et al have also published analyses
suggesting that use of the antiseptic catheter is cost-effective if
the baseline incidence of CVC-related infection is greater than
0.4 per 1000 IVD-days, 327,32s they project that $59 000 will be
saved, seven cases of bloodstream infection avoided and one
death prevented for every 300 antiseptic catheters used.
Raad et al proposed the use of a minocycline-rifampicincoated catheter, based on in-vitro and animal data demonstrating potent activity of this novel combination against
Gram-positive, and Gram-negative organisms and Candida
albicans 329,330 A randomized clinical trial with nearly 300 shortterm CVCs found that the coated catheters were associated
with greatly reduced catheter colonization (8% versus 26%;
p = < 0.001) and CVC-related infection (0% versus 5%;
p = <0.01). 269 N o resistance to the minocycline-rifampicin
combination was detected.
A multicenter trial comparing minocycline-rifampicincoated and chlorhexidine-silver sulfadiazine-impregnated
CVCs found that antibiotic-coated catheters were far less likely
to be colonized at removal (RR 0.34, p < 0.001). 331 While
Kaplan-Meier analysis showed the two catheters to be equivalent with regard to the risk of catheter-related blood infection
until day 7, overall rates of such infection were much lower
among patients with the minocycline-rifampicin-coated
catheter (0.3 versus 4.1 per 1000 IVD-days p = <0.001).
The major theoretical deterrents to using antibiotics for
coating percutaneous intravascular catheters are the ineffectiveness of antibiotics against antibiotic-resistant nosocomial
bacteria and yeasts, the risk of promoting bacterial resistance
with long-term topical use 332,333 and potential for hypersensitization. 334 Although no induction of resistance to minocycline-rifampicin has been identified in the three clinical trials
to date, 269,331,335 an in-vitro study has shown that resistance can
develop. 336 It would seem of high priority that future studies
carefully evaluate the long-term impact of anti-infective-coated
catheters on nosocomial microbial resistance.
Two second-generation silver-impregnated catheters have
been studied clinically. The Erlanger' catheter uses a microdispersed silver technology to greatly increase the quantity of
available ionized silver and has been evaluated in two
trlals. 337,338 Adult patients randomized to the Erlanger" catheter
had lower rates of catheter colonization and rates of 'catheterassociated sepsis' than those in the control catheter arm (5.3
versus 18.3 per 1000 IVD-days, p = < 0.05).
A novel silver-impregnated CVC utilizing oligodynamic iontophoretic technology has also been developed and evaluated
in two clinical trials. This novel catheter incorporates both
silver and platinum in the polyurethane, putatively increasing
the surface release of silver ions. A single randomized clinical
trial, while underpowered, found a trend towards reduced
catheter-related bloodstream infection with the use of this
catheter (4% versus 12%; p = 0.09). 339 A larger trial that used
historical controls, demonstrated rates of CVC-related infec-
593
594
I CHAPTER 45
I NFECTIONS ASSOCIATED WITH IMPLANTED MEDICAL DEVICES
tions in the year after the silver-platinum catheter was introduced markedly lower than rates seen in the years when standard polyurethane CVCs were in use (0% versus 4%; p =
<0.001). 340
Anti-infective hubs
A novel hub developed by Segura et al (Segur-Lock®, Inibsa
Iaboratories) contains a connecting chamber filled with iodinated alcohol and was shown in a randomized clinical trial to
be associated with greatly reduced rates of catheter colonization and CVC-related bloodstream infection (4% versus 16%;
p = <0.01),34' although a subsequent trial failed to show benefit
with the use of this hub. 342 Another model, using a povidoneiodine saturated sponge to encase the hub, also showed significant reductions in CVC-related infection, compared to a
control hub (0% versus 24%, P = <0.05).343
tions on nosocomial colonization by vancomycin-resistant enterococci, MRSA and fluoroquinolone-resistant Gram-negative
bacilli.
Most studies used a lock solution containing vancomycin.
It seems unlikely that micro-organisms in the exposed patient's
flora could develop resistance to vancomycin from the minute
quantities of drug in a catheter lumen (< 15 gg), yet there is
just concern over the possible effect of wide prophylactic use
of vancomycin lock solutions, and more data are needed before
their routine use can be recommended, specifically, randomized studies that prospectively assess the impact on nosocomial
colonization by resistant micro-organisms. However, because
antibiotic lock solutions clearly reduce the risk of implantrelated infections with long-term IVDs, the new HICPAC
Guideline considers their use acceptable in individual cases in
which a patient who requires indefinite vascular access continues to experience such infections despite maximal compliance with infection control guidelines. 313
Antibiotic lock therapy
Prophylactic use of systemic antibiotics at the time of IVD
implantation has not proven effective in reducing the incidence
of IVD-related bloodstream infections and is strongly discouraged. 313 However, studies of continuous infusion of vancomycin, incorporated into total parenteral nutrition
admixtures, have shown reduced rates of coagulase-negative
staphylococcal bacteremia in low-birth-weight infants. 344
Unfortunately, this form of prophylaxis results in prolonged
low blood levels of vancomycin, which may be conducive to
promoting resistance.
The `antibiotic lock' is a novel technique of local prophylaxis: an antibiotic solution is instilled into the catheter lumen
and allowed to dwell for a defined period of time, usually 6-12
hours, after which it is removed. There have been six prospective randomized trials of antibiotic lock solutions for the prevention of bloodstream infections with long-term IVDs. The
largest trial and most recent trial by Henrickson et a1345 randomized 126 pediatric oncology patients (36 944 "-days)
who had recently had a tunneled CVC implanted to three prophylactic lock regimens: heparin (10 U/ml) (control); heparin
and vancomycin (25 gg/ml); and heparin, vancomycin and
ciprofloxacin (2 gg/ml). Use of the vancomycin-ciprofloxacin
containing lock solution was associated with a markedly lower
rate of IVD-related infection, than that with heparin alone
(0.55 versus 1.72 per 1000 IVD-days; p = 0.005). Similarly,
the rate of infection with vancomycin-containing lock solution
was significantly reduced (0.37 per 1000 IVD-days; p = 0.004).
The two antimicrobial lock solutions showed comparable protection against Gram-positive and Gram-negative IVD-related
infection. Unfortunately, failure to separate local infections
from bloodstream infections in the final data limits analysis of
the results of this study. While rates of nosocomial colonization or infection with vancomycin-resistant enterococci, as
detected by clinical cultures ordered by patients' physicians,
were comparable in the three groups, no effort was made to
proactively assess the impact of antibiotic-containing lock solu-
I NFECTION OF CEREBROSPINAL
FLUID SHUNTS
EPIDEMIOLOGY
Cerebrospinal fluid (CSF) shunts are widely used for surgical
decompression and diversion of excess CSF in the management of hydrocephalus. Approximately 25 000 shunt procedures are performed in the USA annually, making it the most
commonly performed neurosurgical operation. 346 While considerable success in the treatment of hydrocephalus has been
achieved, the most serious complication remains infection.
Early studies reported rates of CSF shunt infection ranging
from 1.5 to 39% (mean 10-15%); 347,345 however, during the
past two decades infection rates have dropped to 2-9%. 349-352
Most reported series are from infant and pediatric populations,
as most shunts are placed for treatment of congenital hydrocephalus. Ventricular shunt infection rates range from 3.9 to
5.2%353 in the most recent US national nosocomial infection
surveillance report, with the highest risk in children, particularly premature infants, 354 and elderly people. 349 CSF shunt
infections are associated with a mortality of 20-50%, 355,356 prolonged stay in hospital, and an increased risk of seizure disorder357 and decreased intellectual performance in survivors. 35s
A CSF shunt system consists of a catheter placed either in
the ventricle or the lumbar subarachnoid space which is connected to a subcutaneous silastic tube through which CSF
drains into the central great veins, the pleural space or, most
commonly, the peritoneum. A reservoir to allow percutaneous
access for CSF sampling and intraventricular administration
of antibiotics or chemotherapy may be incorporated (e.g.,
Hakim system) or may be independent (Rickham or Ommaya
reservoir). Pressure-regulating valves are also usually integrated
into the system.
A variety of different shunt systems have been evaluated but
I
I NFECTION OF CEREBROSPINAL FLUID SHUNTS
ventriculoatrial (VA) and ventriculoperitoneal (VP) shunts have
been employed most widely in clinical practice (Figure 45.4).
VP shunting has become the diversion procedure of choice
because of its shorter operative time and the need for fewer
revisions than VA shunts. 359 The rate of infection does not
appear to differ greatly between VA and VP shunts. 360
A number of studies have identified risk factors that predispose to the occurrence of shunt-related ventriculitis or
meningitis. One large, recent prospective study of 299 patients
using multivariable techniques of data analysis found the presence of a CSF leak (odds ratio 19.2), infant prematurity (odds
ratio 4.7) and a breach in surgical asepsis (odds ratio 1.07) to
be the most important risk factors for shunt infection. 363 Other
risk factors include younger age (10-20% rates of infection in
infants <6 months of age) 114,364 and high cutaneous floral
density. 365
rosurgical procedure; hence, the inoculum should be small.
Coagulase-negative staphylococci cause most infections and
are of low intrinsic virulence. Host defenses are severely
impaired, however, because of the foreign body nature of the
shunt. 368 The pressure valves have been found to be the most
heavily colonized portion of an infected shunt. 368
Bacteremia from a remote source can also cause secondary infection of CSF shunts. The frequency of VP shunt
infection by this route is unclear but is thought to be low.
VA shunts, however, are continuously and directly exposed
to potential infection by silent transient bacteremias.
Reports of late Haemophilus influenzae with VA shunts infections in children affirm the potential for hematogenous
infection of these devices. 369
Infection of the distal portion of a VP shunt may derive from
perforation of an intra-abdominal viscus or pelvic inflammatory disease in women, with retrograde extension of infection
throughout the drainage tubing and valve apparatus. 370
Although lumbo-ureteral shunts are now rarely used, retrograde infection by Gram-negative bacilli derive from silent bacteriuria. 3"
MICROBIOLOGY
epidermidis and other coagulase-negative
staphylococci are responsible for the vast majority of CSF
shunt infections, 347,355,372,373 and Staph. aureus causes about
25% of cases (Table 45.5). Gram-negative enteric bacteria
and Pseudomonas spp. account for about 5-10% of infections
and are associated with greater morbidity and mortality. 374
Anaerobic organisms, particularly Propionibacterium species,
account for 3-20% of infections in various series. 3 'S
Polymicrobial infection must prompt suspicion of bowel perforation as the source. 376 Fungal infections, fortunately, are
rare, accounting for less than 1% of infections; C. albicans is
the leading pathogen, 3 " although infections with Coccidioides
immitis, 378 Cryptococcus neoformans 379 and Histoplasma capsulatum38 ° have been reported.
Staphylococcus
Fig. 45.4 Schematic of (A) ventriculoatrial (VA) and
(B) ventriculoperitoneal (VP) cerebrospinal fluid shunts.
PATHOGENESIS
Micro-organisms gain access to the shunt by three routes:
(1) intraoperative colonization; (2) hematogenous seeding of
the shunt; or (3) retrograde spread of infection from the distal
portion of the catheter, such as the peritoneal cavity or bloodstream. Intraoperative contamination of the shunt is widely
considered to be most important, since 80% of infections occur
within 6 months of surgery. 347-349 Bayston et al compared
organisms cultured from the surgical wound at the time of
shunt insertion or revision with those cultured from the
patient's nose, ear or skin before operation: 366 58% of wounds
were colonized, and in one-half the colonizing organism originated from the patient's own flora. The level of contamination of the wound was directly proportional to the duration of
the surgical procedure. More recently, airborne bacteria in the
operating room have been identified as an important source of
shunt infection. 367
Three factors play a central role in the development of shunt
infection: the microbial inoculum; microbial virulence, and the
patient's host defenses. CSF shunt implantation is a clean neu-
Table 45.5 Microbiologic profile of CSF shunt infectionsa
Organism
Staphylococcus epidermidis
Staphylococcus aureus
Streptococcal species
Enteric Gram-negative bacilli
Anaerobes
Diphtheroids
Organisms of traditional meningitisb
Pooled data.347,355.372,373
b H. influenzae, Str. pneumoniaeand N. meningitidis
a
Incidence
60-70
1 2-25
8-10
6-20
6
1 -14
2-8
(°lo)
595
59 6
I CHAPTER 45
I NFECTIONS ASSOCIATED WITH IMPLANTED MEDICAL DEVICES
DIAGNOSIS
The clinical manifestations and diagnostic approach to shunt
infections vary, depending in part on the type and location of
the shunt. Fever is the most common manifestation of infection with all types of shunts but is not universally present, especially if the infecting organism is CNS. 347,381 With proximal
infection (ventriculitis), headache may be absent and non-specific symptoms such as lethargy and malaise may be the only
clinical clues to infection; meningismus is present in less than
one-third of cases. 382
Complications of VA shunt infections include septic pulmonary emboli, 383 perforation of the myocardium leading to
tamponade '384 perforation of the interatrial septum, superior
or inferior vena caval obstruction, 385 atria] thrombus 386 and
right-sided endocarditis. 387 A rare manifestation of chronic VA
shunt infection is shunt nephritis, 388 caused by deposition of
antigen-antibody complexes onto the glomerular basement
membrane, similar to the immune complex nephritis of bacterial endocarditis. The nephritis characteristically resolves
when the underlying shunt infection is eradicated. 388
Up to one-third of patients with VP shunts present with
abdominal symptoms. A loculated CSF collection often develops; however, if encystation by the peritoneum is unsuccessful, frank peritonitis may occur. 389 The presence of a peritoneal
pseudocyst in a patient with a VP shunt almost always indicates shunt infection. 39 ° VP shunts are also well known to
spontaneously perforate the bowel. In the early postoperative
period, local signs of inflammation with wound infection or
infection of the subcutaneous course of the drainage tubing
may be present. The first indication of occult infection is often
shunt malfunction. 391 Occult infection must be ruled out in
every case of shunt malfunction.
The diagnosis of shunt infection requires a high index of
suspicion because of its insidious and frequently nonspecific
presentation. Fever in a shunted patient should always prompt
suspicion of shunt infection. Blood cultures reliably identify
the causative organism in 95% of VA shunt infections; 392 in
contrast only 20% of VP infected shunts produce bacteremia. 348
The peripheral white blood cell count (WBC) is of limited
value in diagnosing shunt infection; up to 25% of patients have
a normal WBC count. 393 CSF leukocytosis is also usually
modest: one study reported a median CSF WBC count of
79 cells/mm 3 . 348 Gram-stained smears of CSF were positive in
the majority of cases of infection with Staph. aureus and Gramnegative bacilli (82% and 91% respectively) but in only a minute
fraction of cases (4%) caused by coagulase-negative staphylococci. 372 Other CSF changes are rarely helpful in the diagnosis:
hypoglycorrachia is infrequent and slight, when present; 394
protein elevation is often present but is non-specific. 372
Cultures of CSF obtained from the shunt are essential to
establish the diagnosis and are positive in 90% of patients when
pleocytosis is > 100 white cells/mm 3, but only 50% of patients
when pleocytosis is <20 white cells/mm 3 . 347 The highest yield
is when the CSF is aspirated directly from the shunt (92%). 394
Radiologic imaging is useful if the patient has abdominal
symptoms or a palpable mass, to evaluate for the presence of
a peritoneal pseudocyst, which almost always signifies infection. If the shunt is malfunctioning, brain imaging may show
hydrocephalus.
TREATMENT
Management of the shunt
Once CSF shunt infection is diagnosed, usually by a positive
CSF culture, options for treatment include;
complete removal of the shunt apparatus, delaying replacement until the infection has been eradicated with parenteral
antibiotics;
surgical removal of the shunt, temporary external CSF
drainage, parenteral antimicrobial therapy, with shunt
replacement after the infection has been eradicated;
externalization of distal portion of shunt (for VP shunts),
followed by delayed replacement, in conjunction with systemic antimicrobial therapy;
retention of shunt, attempting to eradicate the infection with
antibiotic therapy alone.
All of these approaches, except the last, subject the patient
to one or more surgical procedures, with attendant risks. The
most widely accepted approach has been complete removal of
the entire shunt apparatus, followed by prolonged antimicrobial therapy, with later implantation of a new shunt on the
contralateral side. 356,372,381,395 If CSF drainage is necessary
during the interim period temporary external CSF drainage
can be provided with a ventriculostomy catheter.
In a prospective randomized study, James et al compared
three groups of patients with VP shunt infections who were
treated by three different approaches: 355 one group underwent
shunt removal, systemic antibiotic therapy and external ventricular drainage; the second, shunt removal with immediate
shunt replacement, followed by intrashunt antibiotic therapy;
and the third, systemic and intraventricular antibiotic therapy
alone without shunt removal. The cure rates were 100%, 90%
and 30%, respectively. The group that received antimicrobial
therapy alone had a much longer hospital course and two of
the ten patients died. Larger retrospective series have corroborated these results (Table 45.6), and removal of an infected
shunt is considered mandatory to achieve reliable cure of shunt
infections. 347,392
McLaurin et al have suggested that some VP shunt infections may be cured without removing the ventricular portion
of the apparatus, by externalizing the peritoneal catheter and
closed system drainage, combined with intraventricular and
systemic antimicrobial therapy; 396 of 11 patients with VP
shunts (age range three weeks to 14 years), 10 were reportedly cured of infection with this approach. Follow-up periods
ranged from 4 months to 5 years. However, in a more recent
study, externalization of distal tubing with retention of the
I NFECTION OF CEREBROSPINAL FLUID SHUNTS I
Table 45.6 Cure rates with different approaches to
management of CSF shunt infection: an analysis of 20 series
published between 1975 and 1987a
Antibiotics
alone
Antibiotics
Antibiotics
+ shunt removal
+ immediate shunt
+ shunt removal
replacement
ventriculostomy
+ external
+ delayed shunt
replacement
No. treated
No. cured
a
254
95(37%)
Adapted from Bisno and Sturnau,1994.
1 61
227
114(71%)
213(94%)
548
shunt and systemic antimicrobial therapy in patients with VP
shunt infections showed persistently positive CSF cultures in
10 of 21 patients. 397 The most common infecting organisms
were coagulase-negative staphylococci.
Meningitis due to fastidious, highly sensitive organisms that
reach the CSF from the primary bloodstream infections (e.g.
H. influenzae, Str. pneumoniae and Neisseria meningitidis) has
been treated successfully without shunt remova1. 369
Antimicrobial therapy
Several factors must be taken into consideration when choosing systemic antimicrobial therapy, including: CSF penetration of the agent; susceptibility of the infecting organism; and
the potential for neurotoxicity. Nearly 90% of coagulase-negative staphylococcal infections acquired in the hospital implicated in shunt infections are now resistant to methicillin, 353
and vancomycin is thus the drug of choice for most Gram-positive infections. Although its CSF penetration is modest, with
meningeal inflammation it is usually possible to achieve therapeutic CSF levels.398 Rifampicin is often added for enhanced
bactericidal activity, high CSF penetration, in-vitro synergism
with vancomycin and ji-lactams, and its adjunctive value in
other device-related infections. 1 05,125-127 For Gram-negative
infections, group 4 cephalosporins or carbapenems, such as
i mipenem, provide effective treatment if the infecting organism is susceptible, however, with imipenem use in the setting
of meningitis or ventriculitis, the risk of seizures is considerable (33% in some series); 99 meropenem appears to pose a
lower risk . 400
Intraventricular antimicrobial therapy has been extensively
used in the past, with or without systemically administered
antibiotics for treatment of CSF shunt infections, although the
indications for intraventricular therapy are uncertain. 401 The
most commonly used intraventricular antimicrobials have been
the aminoglycosides and vancomycin.
Intrathecal aminoglycosides have been widely used for the
treatment of shunt infections, 402 however, ototoxicity has been
encountered, 402,40a and no randomized trials have confirmed
their benefit. The only prospective randomized trial to compare systemic to intrathecal administration of gentamicin, a
study of neonates with Gram-negative meningitis, showed that
mortality was higher in infants given intrathecal gentamicin
(43%) than in those given systemic gentamicin (13%). 404 Some
authors have recommended routine measurement of CSF
aminoglycoside levels to reduce the risk of toxicity; however,
accurate measurement of CSF drug levels is fraught with difficulty 401 and studies have failed to show a correlation between
toxicity and CSF aminoglycoside levels, 405 even with peak levels
as high as 450 mg/1 406 and trough levels as high as 76 mg/1. 40'
No prospective studies have compared the efficacy of
intrathecal vancomycin with systemic vancomycin, although
anecdotal reports suggest that intrathecal vancomycin therapy
is beneficia1. 40s,409 Vancomycin penetrates the CSF poorly in
the absence of inflammation, 410 and even in the presence of
inflammation attains CSF levels only one-fifth of those it
reaches in serum . 411 Vancomycin typically is administered
intrathecally in doses of 5-20 mg per 24 h. There have been
no reports of neurotoxicity, even with CSF levels as high as
100 mg/1. 364
Intraventricular R-lactams and cephalosporins cause seizures
and neurological deficits and their use is strongly discouraged. 412
Antimicrobials given intrathecally should be constituted in
a preservative-free medium to reduce the risk of arachnoiditis.
In general, removal of the infected shunt and intravenous antibiotic therapy will prove effective in the vast majority of cases,
and intraventricular antibiotic therapy should be used only if
there is reason to believe that therapeutic CSF concentrations
cannot be achieved with systemically administered antibiotics,
such as in patients with severe scarring of the choroid plexus
or if the antimicrobial of choice is known to have poor CSF
penetration, such as an aminoglycoside.
There is a paucity of clinical data regarding the duration of
therapy for CSF shunt infections; a minimum of 7 days has
been suggested, with the final duration influenced by the rapidi ty of clinical improvement and results of serial CSF cultures. 364
PREVENTION
As it appears that intraoperative contamination by skin flora
or airborne skin organisms is the most important mechanism
of infection of CSF shunts, efforts have been directed at
improving intraoperative asepsis and reducing contamination
of the operative field. Novel measures that have been evaluated include adhesive plastic drapes, 413 use of ultraviolet lights
in the operating room,414 soaking shunts in an antimicrobial
solution415 and irrigating the wound with an antibiotic solution. 416 None has been evaluated in a randomized trial, and
thus most cannot be routinely recommended.
Faillace et al reported a meticulous 'no-touch' protocol for
CSF shunt implantation, 417 which involved minimal handling
59 7
598
I CHAPTER 45
I NFECTIONS ASSOCIATED WITH IMPLANTED MEDICAL DEVICES
of shunt components during implantation through use of
special instruments, placing the shunt on a separate table away
from skin dissection instruments, limiting the number of personnel in the operating room, and intensive education of surgical assistants and nurses: a threefold decrease in the rate of
shunt infection was observed, from 9.1% before implementation of the new protocol to 2.9% (odds ratio 0.30; P = 0.05).
Choux et al employed an even more intensive perioperative
protocol, including not shaving the operative site, using
chlorhexidine or povidone-iodine for site disinfection, implantation early in the morning before other operations, single-dose
perioperative prophylaxis, meticulous surgical technique and
limiting the implantation procedure to 40 minutes. 41s With
adoption of these measures, the authors observed a decreased
infection rate from 7% to 0.2%. However, because so many
modifications of the surgical procedure were made, it is difficult to draw conclusions about the independent role of each
measure. While most neurosurgeons shave their patients preoperatively, randomized trials have shown that shaving may
increase the risk of CSF shunt infection. 419
The use of perioperative prophylactic antibiotics for shunt
implantation procedures has been controversia1. 420 Most
studies have suffered from methodologic problems: most were
uncontrolled, retrospective comparisons. Few of the randomized trials done were adequately powered to detect a clear-cut
benefit from use of preoperative prophylactic antibiotic
therapy. In one prospective trial of 243 patients undergoing
300 CSF shunt implantations, oral trimethoprim and
rifampicin were administered 2 h before surgery and for 48 h
postoperatively. 421 A lower infection rate (12%) was found in
the treatment group than the placebo group (19%); however,
the results did not achieve statistical significance. In another
randomized trial, Blomstedt reported significantly fewer infections among patients receiving perioperative trimethoprim-sulfamethoxazole than those receiving placebo; 422 however,
children less than 12 years of age were excluded from the
study, and the 29% baseline rate of infection is very high.
Bayston et al determined that a randomized trial with power
to detect a statistically significant difference, if one exists,
would require 712 patients. 423 Their multicenter trial was not
able to achieve this goal and was terminated after 2.5 years. 423
Several meta-analyses have attempted to resolve this
issue. 350,424,425 Two suggest benefit; 424,425 one early and smaller
meta-analysis did not: 350 Haines et al found a 50% risk reduction from prophylactic antibiotic use with a baseline infection
rate above 5%;425 Langley et al in a meta-analysis of 12 randomized trials came to a similar conclusion. 424 It thus appears
that short-term perioperative antimicrobial prophylaxis may
be of benefit in preventing shunt infections: anti-staphylococcal
antibiotics, such as cefuroxime or trimethoprim-sulfamethoxazole, are recommended.
Novel technology
Incorporation of antibiotics into the shunt material has been
attempted to decrease the incidence of shunt infection. Bayston
et al demonstrated that impregnation of silicone rubber with
clindamycin hydrochloride was effective in preventing in-vitro
bacterial colonization by Staph. epidermidis for as long as 9
days . 426 The same authors also showed that catheters impregnated with clindamycin and rifampicin resisted three successive challenge doses of Staph. epidermidis over a 28-day
period427 as well as biweekly challenges with strains of Staph.
aureus and Staph. epidermidis over periods as long as 56 days. 42 a
While these in-vitro studies are promising, the efficacy, thrombogenic and epileptogenic potential of medicated shunts must
be evaluated by randomized clinical trials before they can be
recommended.
An ineffective immune response against infection in infants
is thought to contribute to the higher infections rates of CSF
shunts in patients less than one year of age. A prospective randomized trial of administering a single dose of intravenous
immunoglobulin prior to shunt implantation in infants showed
a lower rate of infection in the group given immunoglobulin
(0 versus 5.1%), however, the study was underpowered (60
patients), and the results did not achieve statistical significance.429
VENTRICULOSTOMY-RELATED
I NFECTIONS
EPIDEMIOLOGY
Intracranial pressure monitoring has become essential for the
management of patients with closed head injuries or who have
undergone major neurosurgical operations. 430,431 Techniques
used to measure intracranial pressure include use of ventriculostomy catheters (72%), intraparenchymal catheters (47%),
subarachnoid bolts (25%), epidural catheters (15%) and subdural catheters (5%). 432 The most accurate and widely used
method to continuously measure intracranial pressure is by
placement of an intraventricular catheter through a burr hole
into the lateral ventricle. Unfortunately, ventriculostomy
catheters are associated with a substantial risk of ventriculitis
and meningitis, which has significant morbidity. 431,433
Infection is the primary complication associated with the
use of ventriculostomies, ranging from 0 to 40%. 433-440 Most
studies average 10% 431 and a large meta-analysis, which included more than 6000 patients, found an overall rate of infection
of 5.8%.441 Prospective studies indicate that the greatest risk
factor for development of ventriculostomy-related infection is
the duration of ventricular catheterization. 433,437 Mayhall et al,
in the largest prospective study, found that the risk of infection rose to 9% after 5 days of catheterization (RR, 7.0). 433
Paramore et al found that the rate of infection rose to 10.3%
by the sixth day. 430 Irrigation of the system, 433 intracerebral or
intraventricular hemorrhage (RR 3.5) 433,43 ' and high intracranial pressures 433 have also been found to increase the risk
of nosocomial ventriculitis.
CATHETER-ASSOCIATED URINARY TRA CT I NFECTIONS
PATHOGENESIS AND MICROBIOLOGY
The pathogenesis of ventriculostomy-related infection is poorly
understood: infecting organisms can be introduced at the time
of catheter insertion, but probably more often gain access
during later manipulation of the system for CSF drainage or
calibration. 440
Ventriculostomy-related infection is very similar to postoperative neurosurgical wound infection. The most common
infecting micro-organisms have been coagulase-negative
staphylococci and Staph. aureus, which cause 60-80% of all
caseS; 433,442 however, a significant number of cases of nosocomial meningitis are caused by Gram-negative bacilli, ranging
from 16 to 33%. 443,444
of prophylactic antibiotics with prolonged prophylaxis, in
which the patients received therapy for the entire period of
catheterization, and showed a lower infection rate in patients
receiving prolonged prophylaxis with ampicillin-sulbactam and
aztreonam (3% versus 11%, P = 0.01). 445 However, the
pathogens causing infection in patients receiving prolonged
prophylaxis showed greater antimicrobial resistance. Two other
randomized trials, one in 52 patients and the other in 95
patients, did not demonstrate any benefit from prophylactic
antibiotic use, but the studies were severely underpowered. 422,446 Prophylactic antibiotics to prevent monitoringrelated ventriculitis with ventriculostomy catheters are probably
not effective, are likely to promote infection by multiresistant
pathogens, and based on current data, are not recommended.
TREATMENT
Similar to the treatment of CSF shunt infections, the treatment of ventriculostomy-related infection should be guided by
the results of the CSF Gram-stain and culture. If feasible, the
catheter should be removed unless intrathecal therapy is considered essential (e.g. for Ps. aeruginosa ventriculitis). For most
nosocomial staphylococcal infections, intravenous vancomycin
and oral rifampicin are required, unless in-vitro susceptibility
testing shows susceptibility to (3-lactams.
For ventriculitis caused by Gram-negative bacilli, a
cephalosporin such as cefepime or cefotaxime or a carbapenem (meropenem, rather than imipenem, given the higher risk
of seizures with the latter4°°), with or without ciprofloxacin,
should prove effective in most cases.
As noted, the role of intraventricular antimicrobial therapy
in the treatment of CSF infections related to neurosurgery is
undefined, but its use should be considered in patients who
fail to improve despite the use of appropriate systemic antimicrobial therapy.
PREVENTION
Prevention of catheter-related ventriculitis begins with limiting the duration of catheterization to the fewest days necessary
and maintaining a stringently closed system. Mayhall et al have
recommended relocating the ventricular catheter to a new site
if monitoring exceeds 5 days; 433 however, the risks associated
with placement of a new ventriculostomy catheter, especially
intracranial hemorrhage, have been estimated to be as high as
6% . 430
Data on the prophylactic use of antibiotics at the time of
catheter insertion and/or throughout the duration of ventricular catheterization are also conflicting. Of five retrospectlve431,434-436,438 and two prospective trlalS, 433,437 only two
retrospective studies found the use of antimicrobial prophylaxis to be beneficial. 434,435
One randomized trial in 228 patients receiving ventriculostomy catheters compared brief perioperative administration
CATHETER-ASSOCIATED URINARY
TRACT INFECTIONS
EPIDEMIOLOGY
Catheter-associated urinary tract infections (CAUTIs) account
for 40% of all nosocomial infections in the USA, affecting an
estimated 800 000 patients per year. 447 In the 25% of patients
that have a urinary catheter inserted at some time during their
hospital stay the incidence of nosocomial UTI is approximately
5% per day, with virtually all patients developing bacteriuria
by 30 days of catheterization. 448 Even though the vast majority of these infections are asymptomatic, 449 silent CAUTIs
comprise the largest pool of antibiotic-resistant pathogens in
the hospita1353 and drive a great deal of generally unnecessary
antibiotic therapy.
Large, prospective studies in which catheterized patients
were cultured daily and which used multivariable techniques
of statistical analysis have identified risk factors independently
predictive of an increased risk for CAUTI: 45°-453 females have
a higher risk than males (RR, 2.5-3.7), and patients with other
active sites of infection (RR, 2.3-2.4) or a major pre-existing
chronic condition such as diabetes (RR, 2.2-2.3), malnutrition (RR, 2.4), or renal insufficiency (RR, 2.1-2.6), are also at
higher risk; inserting the catheter outside the operating room
(RR, 2.0-5.3) or late in hospitalization (RR, 2.6-8.6), the presence of a ureteral stent (RR, 2.5) or using the catheter to
measure urine output (RR, 2.0) further increase risk. The most
important modifiable risk factor, identified in every study, is
prolonged catheterization - beyond six days. Antimicrobial
therapy is protective against CAUTI for short-term catheterizations (RR, 0.1-0.4) but clearly selects for infection caused
by multiresistant micro-organisms such as Ps. aeruginosa and
other resistant Gram-negative bacilli, enterococci and yeasts.
A recent large, prospective study monitored compliance on
a daily basis with seven recommended precepts for catheter
care, including closed drainage, proper position of the drainage
tubing and collection bag, and protection of the drainage
I
S99
)o I CHAPTER 45
I NFECTIONS ASSOCIATED WITH IMPLANTED MEDICAL DEVICES
port.453 The only violation predictive of an increased risk of
CAUTI was improper position of the drainage tube, above the
level of the bladder or sagging below the level of the collection
bag. This study suggests we may be at the point of diminishing returns in terms of behavioral modification for further
reduction in CAUTI, and that technologic innovations will be
needed to further reduce risk.
PATHOGENESIS
Excluding rare hematogenous pyelonephritis, most CAUTIs
derive from micro-organisms in the patient's own colonic and
perineal flora or transmitted from the hands of healthcare
personnel during catheter insertion or manipulation of the
collection system. 447,44s Organisms gain access extraluminally
- by direct inoculation when the catheter is inserted or later,
by organisms ascending from the perineum by capillary
action in the thin mucous film contiguous to the external
catheter surface - or intraluminally, by reflux of micro-organisms gaining access to the catheter lumen from failure of
closed drainage or contamination of collection bag urine
(Figure 45.5). Recent studies suggest that CAUTIs most frequently are extraluminally-acquired, but both routes are
important . 454
Infected urinary catheters are covered by a thick biofilm,
which forms intraluminally, extraluminally or both, usually
advancing in a retrograde fashion. Anti-infectioe-impregnated
and silver-hydrogel catheters, which inhibit adherence of
micro-organisms to the catheter surface, significantly reduce
the risk of CAUTI, 455-451 particularly infections caused by
Gram-positive organisms or yeasts, which are most likely to be
acquired extraluminally from the periurethral flora. These data
suggest that microbial adherence to the catheter surface is
i mportant in the pathogenesis of many, but not all, CAUTIs.
Extraluminal
• Early, at insertion
• Late, by capillary action
t__
J
I ntraluminal
• Break in closed drainage
• Contamination of collection bag urine
Fig. 45.5 Routes of microbial colonization in the pathogenesis
of catheter-associated urinary tract infections (adapted from Maki
and Tambyah, 2001 447 ).
Infections in which the biofilm does not play a pathogenic role
are probably caused by mass transport of intraluminal contaminants into the bladder by reflux of microbe-laden urine
when a catheter or collection system is moved or manipulated.
MICROBIOLOGY
As noted, CAUTIs comprise the largest institutional reservoir
of nosocomial antibiotic-resistant pathogens,' 13,441 the most
i mportant of which are multidrug-resistant Enterobacteriaceae
other than Escherichia coli (such as Klebsiella, Enterobacter,
Proteus, and Citrobacter spp.) Ps. aeruginosa, enterococci and
staphylococci, and Candida spp. (Figure 45.6).
DIAGNOSIS
Clinical presentation
Classically, urinary tract infections (UTIs) in non-catheterized
patients present with dysuria and frequency, often associated
with lower abdominal pain or even flank pain. The irritating
effects of a urinary catheter can mimic some of these symptoms in the absence of infection, and thus corroborating evidence of CAUTI is needed before initiation of antimicrobial
therapy.
Although there have been recommendations to treat
CAUTIs only when they are symptomatic, 264 until recently the
symptoms associated with CAUTI had not been clearly
defined. In a recent prospective study of 1497 newly catheterized patients, over half of whom were in an ICU, undertaken
to determine the prevalence of signs and symptoms attributable to CAUTI and the relative contribution of CAUTI to
nosocomial bloodstream infections, quantitative urine cultures
and urine leukocyte counts were taken daily and each patient
was questioned by a research nurse regarding symptoms. 449 In
this study, there were no significant differences between
patients with and without CAUTI in subjective symptoms
commonly associated with urinary tract infection; most were
afebrile. There were also no significant differences between the
two groups in mean peripheral leukocyte counts, although the
urine WBCs in patients with CALM were significantly higher
than in uninfected catheterized patients. Of 79 nosocomial
bloodstream infections identified in the study population, there
was only one that appeared unequivocally to have derived from
a CAUTI; interestingly, this patient had no symptoms referable to the urinary tract.
This study shows that, although a large proportion of
patients with indwelling urinary catheters develop bacteriuria,
fewer than 10% with microbiologically documented CAUTI
(most with active infection and pyuria for many days) report
any symptoms commonly associated with community-acquired
UTI unrelated to a urinary catheter, such as dysuria, urgency,
fever or chills. Symptoms referable to the urinary tract not only
are infrequent in patients with UTI but also have little pre-
CATHETER-ASSOCIATED URINARY TRACT INFECTIONS
Coagulase-neg staphylococci
I
3%
Staphylococcus aureus
Enterococcus
Pseudomonas aeruginosa
Klebsiellal Enterobacter spp.
Esch. coli
Other Gram-negative bacilli
Candida spp.
Fig. 45.6 Microbiologic profile of catheter-associated urinary tract infection, based on
data from the National Nosocomial Infection Surveillance system report. 3 s 3
dictive value for the diagnosis of infection. Moreover, despite
their ubiquity, CAUTs only rarely cause secondary bloodstream infection.
An association between fever and CALM has not been convincingly demonstrated in other studies. In a prospective study
of elderly patients in nursing homes, Kunin et al found that,
although 74% of catheterized patients ultimately developed
CAUTI, fewer than 2% had temperatures higher than
381C.459 More recently, in a study of the contribution of
CAUTI to febrile morbidity in a long-term care facility,
CAUTI was found to be the cause of fewer than 10% of
episodes of fever, despite the high prevalence of bacteriuria. 46o
Warren et al evaluated 47 women in a nursing home with longterm urinary catheters, all of whom had chronic bacteriuria,
and reported a very low incidence of febrile episodes of urinary
tract origin. 461
All of these data show clearly that although CAUTI is
common in catheterized patients, including in the ICU, fever
and symptoms referable to the urinary tract are very infrequent
in patients with UTI and have little predictive value for the
diagnosis of infection.
Laboratory tests
Pyuria has become universally regarded as an essential criterion for the diagnosis and management of urinary tract infection in the non-catheterized patient. 462 However, studies that
have examined the utility of quantitative pyuria in catheterized
patients have found conflicting results on its prognostic
value.463,464 In a study of 761 hospital patients with newly
inserted indwelling urinary catheters, 465 Tambyah et al found
that 82 (10.8%) patients studied developed CAUTI while
catheterized, and the mean urine WBC in patients with
CALM was significantly higher than in patients without infection (71 vs. 4 per mm 3; P = 0.006). However, using a urine
WBC count greater than 10 per mm3 (>5 per high-powered
field in a conventional urinalysis) as the cutoff for defining its
presence, pyuria had a specificity of 90% for predicting
CAUTI with > 10 5 cfu/ml but a sensitivity of only 37%.
The clinical relevance of this study seems clear: pyuria
cannot and should not be used as the sole criterion for obtaining a urine culture in the catheterized patient. This is especially
true in the case of infections caused by yeasts or Gram-positive
COCC1, 466,467 which account for nearly one-half of nosocomial
CAUTs in the ICU. It is clear that most patients with CAUTI
are asymptomatic and do not have fever.449 If a catheterized
patient develops fever or signs of sepsis that cannot be linked
to another source such as nosocomial pneumonia, surgical site
infection or vascular catheter-related infection, 264 urine cultures should be obtained even if the patient does not have
demonstrable pyuria.
In the outpatient setting, particularly in clinics that may
not have rapid access to laboratory testing, non-cultural rapid
diagnostic tests are widely used, most commonly the leukocyte esterase and bacterial nitrite rapid dipstick tests. These
tests have shown excellent sensitivity in non-catheterized
patients with a high pre-test probability of UTI because of
characteristic symptoms; however, in a non-selected patient
population sensitivity of the tests has been poor, in the range
of 50%.468 In a recent prospective study of the leukocyte
esterase and nitrite urinary dipstick in catheterized ICU
patients, the sensitivity (50 and 79%), specificity (48 and
55%), and predictive value (60 and 81%) of both tests were
poor. 46
Gram stains of urine, of either unspun or centrifuged speci mens, have high sensitivity and specificity for detection of
high-level quantitative bacteriuria (> 105 CFU/per ml), with
specificity and positive and negative predictive values all greater
than 90%. 47° However, inexplicably, clinicians encountering
patients with symptomatic UTI or even frank urosepsis rarely
use Gram stains. A Gram stain of urine is simple, can be done
rapidly, and is highly reliable (>90%) for detecting bacteriuria
or candiduria; moreover, it permits immediate determination
of whether the infection is caused by Gram-negative bacilli,
601
502
I CHAPTER 45
I NFECTIONS ASSOCIATED-WITH IMPLANTED MEDICAL DEVICES
Gram-positive cocci such as enterococci or staphylococci, or
yeasts, such as Candida Spp.
Microbiologic studies
In clinical practice, a quantitative culture of a spontaneously
voided, clean-catch urine specimen showing >10 1 cfu/ml is
widely considered to represent infection . 462 Studies have shown
that a count > 102 cfu/tnl of enteric Gram-negative bacilli recovered in culture of a clean catch specimen from a woman with
pyuria and symptoms of UTI correlates highly with recovery
of the same organism from bladder urine obtained by urethral
catheterization or suprapubic aspiration, and can reliably be
considered to represent true lower urinary tract infection, i.e.
cystourethritis. 4"
Because urine cultures obtained by aspiration from an
indwelling urethral catheter bypass potentially contaminating
periurethral flora, it seemed likely that microbiologic concentrations considerably below 105 cu/ml in a culture of urine
taken from a catheterized patient might well be relevant
pathogenetically, epidemiologically, and clinically. In a
prospective study of 110 newly catheterized patients, lowlevel bacteriuria or candiduria (<105 cfu/ml), which developed in 41 patients, progressed to concentrations
>10 5 cfu/m196% of the time (P<0.001), usually within 3 days
of the first culture showing growth, unless the patient
received intercurrent, suppressive antimicrobial therapy. 472
Even with very low-level bacteriuria or candiduria (1-99
organisms per ml), 90% of the cases progressed to high-level
bacteria within 48-72 h, demonstrating that in the catheterized patient a considerably lower level of bacteriuria than
105 cfu/ml, (probably >- 10 2 cfu/ml) is valid as an index of
infection; 102 cfu/ml is a concentration that can be easily and
reproducibly detected in a clinical laboratory.
In sum, a quantitative urine culture showing growth but less
than 105 cfu/ml should not reflexly be disregarded, especially
if the patient is immunologically compromised or has clinical
signs of UTI. In this circumstance, the culture result may reasonably form the basis for antimicrobial therapy if symptomatic
CAUTI or, especially, urosepsis is suspected clinically.
TREATMENT
Only patients with symptomatic CAUTI should receive antimicrobial therapy; however, two clinical exceptions to this
dictum exist: asymptomatic CAUTI in patients who are profoundly granulocytopenic 473 and patients who have silent
CAUTI in association with urinary tract obstruction. 473
Urosepsis in the presence of obstruction rapidly converts silent
bacteriuria to symptomatic urosepsis, which if unrelieved, culminates in bacteremia and septic shock. Harding et al reported that of 27 catheterized patients with asymptomatic
catheter-associated bacteriuria seven (26%) developed symptoms referable to the urinary tract, but only after the catheter
had been removed .474
In the absence of the above exceptions, empiric therapy may
be initiated, in the symptomatic patient, based on the results
of Gram stain and culture and then modified based on the
results of in-vitro sensitivity testing. The optimal duration of
therapy in patients with symptomatic CAUTI remains undefined, but in general, antimicrobials should be continued for
7-14 days . 475
PREVENTION
Catheter-care practices universally recommended to prevent
or at least delay the onset of CAUTI include 447,44s avoiding
unnecessary catheterizations, using a condom or suprapubic
catheter, having trained professionals insert catheters aseptically, removing the catheter as soon as it is no longer needed,
maintaining uncompromising closed drainage, ensuring dependent drainage, minimizing manipulations of the system and
geographically separating catheterized patients. While entirely
defensible, few of these practices have been proven to be effective by randomized controlled trials.
Systemic antimicrobial prophylaxis with trimethoprimsulfamethoxazole, methenamine mandelate, or especially, a
fluoroquinolone 476 can reduce the risk of CAUTI for shortterm catheterizations. Although use of antimicrobials in this
way may reduce the rate of CAUTI, infections that do occur
are far more likely to be caused by antibiotic-resistant bacteria and yeasts. Since most CAUTs are asymptomatic and do
not result in urosepsis, 449 it is difficult to justify antimicrobial
prophylaxis to prevent asymptomatic bacteriuria.
Novel technology
Many technologic innovations proposed and evaluated during
the past 25 years have not proven beneficial,447,44s including
the use of anti-infective lubricants when inserting the catheter,
soaking the catheter in an antimicrobial solution before insertion, regular meatal cleansing or periodically applying antiinfective creams or ointments to the meatus, continuously
irrigating the catheterized bladder with an anti-infective solution through a triple-lumen catheter or periodically instilling
an anti-infective solution into the collection bag. Bladder irrigation with antimicrobial solution has not only shown no
benefit for prevention but has also been associated with a strikingly increased proportion of CAUTTs caused by micro-organisms resistant to the drugs in the irrigating solution. 332
Given the widely accepted importance of closed catheter
drainage, efforts have been made to seal the connection
between the catheter and collection tubing. An initial trial with
a sealed junction showed modest benefit and suggested a
reduction in hospital deaths; however, follow up studies have
not demonstrated a reduction in CAUTI with a sealed
catheter-collecting tube junction. 477
Medicated catheters, which reduce adherence of microorganisms to the catheter surface, may confer the greatest
benefit for preventing CAUTI. Two catheters impregnated
I NFECTIONS ASSOCIATED WITH PERITONEAL DIALYSIS CATHETERS
with anti-infections have been evaluated clinically, one with the
urinary antiseptic nitrofurazone 4s5 and the other with minocycline and rifampicin. 457 Both catheters showed a significant
reduction in bacterial CAUTIs; however the studies were small
and the impact of the coating on selection of antimicrobialresistant uropathogens was not satisfactorily resolved. Coating
the catheter surface with an antiseptic, such as a silver compound, offers another alternative to reduce the risk of CAUTI.
Silver oxide-coated catheters, however, did not show efficacy
in large, well-controlled trials . 451,452 In one trial, male patients
receiving a coated catheter had a paradoxical and inexplicably
increased risk of CAUTI.452
A silver-hydrogel catheter has been developed that inhibits
adherence of micro-organisms to the catheter surface in vitro
and has also been evaluated clinically. 456,458,478 I n a recent,
large, double-blind trial in 850 patients, the silver-hydrogel
catheter reduced the incidence of CAUTI by 26%, 456 and was
most effective in preventing infections caused by Gram-positive
organisms, enterococci, staphylococci and Candida, microorganisms that appeared to gain access to the bladder extraluminally; the catheter conferred no protection against
CAUTIs with Gram-negative bacilli, which most often gain
access intraluminally. Use of the silver-hydrogel catheter was
not associated with an increased incidence of infections caused
by antibiotic-resistant organisms or Candida, and in-vitro susceptibility testing of isolates from both treatment groups
showed no infections caused by silver-resistant micro-organisms. Cost-utility analysis indicates that use of this catheter
could bring substantial cost savings to healthcare institutions.447 In a large crossover trial of a silver-hydrogel catheter
in 27 878 patients, Karchmer et al also found a lower risk of
CAUTI with the novel catheter (RR 0.70; p = 0.04).458
I NFECTIONS ASSOCIATED WITH
PERITONEAL DIALYSIS CATHETERS
I
and 80% will have experienced at least one episode by 30
months. 484
PATHOGENESIS
Infection of the peritoneum occurs by one of several routes: 485
intraluminal contamination of the catheter during dialysate
exchange, migration of skin micro-organisms in the space contiguous to the external surface of the catheter, transmural
migration of intestinal organisms, hematogenous seeding,
extrinsic contamination of dialysate (mainly in association with
CCPD) and transvaginal spread.
Considerable evidence suggests that most infections derive
from contamination of the PD catheter, either extraluminally
or, more often, intraluminally by the patient's endogenous skin
flora: surveillance cultures from the patients' skin and peritoneal fluid have shown concordance, 486 use of Y systems,
which reduce the number of times that patients are required
to open their drainage system, has resulted in a significant
decline in the incidence of CAPD. 48'49° Use of CCPD, which
requires patients to access their PD catheters only once a day,
has similarly been associated with reduced rates of peritonitiS.482,491 Finally, nasal carriers of Staph. aureus are more likely
to develop concurrent Staph. aureus exit-site infections and
peritonitis .412,493
The presence of a foreign body that is exposed to the external environment is the primary reason for the high rates of
infection with PD; however, the presence of a large volume of
non-physiologic fluid in the peritoneum impairs local host
defenses, further increasing the risk of infection. Intraperitoneal
activated macrophages and opsonins - immunoglobulin G and
complement (C3) - are found in greatly reduced concentrations with repeated dialysate exchanges. 494,49 s The high osmolarity and low pH of the dialysate, which has been shown to
reduce granulocytic function in vitro, 496 may also contribute
to susceptibility to infection.
EPIDEMIOLOGY
MICROBIOLOGY
It is estimated that 115 000 patients worldwide were maintained on peritoneal dialysis (PD) in 1997. 4' 9 Nearly two-thirds
of patients maintained on peritoneal dialysis in the United
States receive continuous ambulatory PD (CAPD) while the
remainder receive their dialysis by other mechanisms, such as
continuous cycler PD (CCPD). 479
Infection is the most common complication of PD, occurring at the catheter exit site; the catheter tunnel; or the peritoneum. Infection of the catheter exit site and the tunnel are
relatively unusual but infection of the peritoneum is very
common and remains the leading indication for conversion to
hemodialysis in this population . 480 Between 63 and 90% of
patients undergoing CAPD retain their catheters for 3
years, 481483 although at least 60% will experience an episode
of peritonitis within the first 12 months of initiating dialysis,
Table 45.7 summarizes the range and frequencies of pathogens
causing PD-related peritonitis. Gram-positive organisms
account for 60-80% of culture-proven cases. Unusual organisms include Alcaligenes xylosidans, Stenotrophomonas maltophilia, Burkholderia cepacia, Agrobacterium spp., Mycobacterium
spp., and Fusarium spp.
In approximately 20% of cases, cultures of the peritoneal
fluid fail to grow any organisms despite the presence of a large
number of inflammatory cells. These patients usually respond
to empiric antimicrobial therapy.
Staph. aureus accounts for approximately 50% of PD
catheter exit site and tunnel infections, and coagulase-negative
staphylococci are implicated 1n 30%.479 In contrast to surgical
peritonitis, Gram-negative bacilli are less commonly involved
with PD catheter exit site and tunnel infections, with Ps. aerug-
603
604
I CHAP TER
45
I NFECTIONS ASSOCIATED WITH IMPLANTED MEDICAL DEVICES
Table 45.7 Distribution of micro-organisms causing peritoneal
dialysis-related peritonitis a
Organisms
Coagulase-negative staphylococci
Staphylococcus aureus
Streptococcus spp.
Enterococci
Escherichia coli
Pseudomonas spp.
Other Gram-negative bacilli
Anaerobic organisms
Fungi
Other
Culture negative
4
30-40
1 0-20
1 0-15
3-6
5-10
5-10
7-16
2-5
2-10
3-7
0-30
Adapted from Vas, 1994.486
inosa and Esch. coli being isolated in 8% and 4% of cases,
respectively.479
thought to most often represent a failure of culture methods
rather than infection with an unusual organism. 503 The most
common mistakes are obtaining cultures too early in the course
of peritonitis, before microbial counts rise to detectable levels;
culturing inappropriately small volumes of dialysate
(<10 ml); 504 and administration of antibiotics before obtaining cultures. 50s Persistently elevated cell counts despite appropriate empiric antibiotic therapy should raise suspicion of an
unusual pathogen, such as M. tuberculosis or fungi, especially
if monocytosis or eosinophilia is present, or a non-infectious
cause, such as renal cell carcinoma, leukemia or peritoneal
lymphoma. 479
Plain films and CT scans of the abdomen are generally not
useful or recommended, and often reveal a small volume of
pneumoperitoneum that does not represent bowel perforation.
However, if the patient presents with signs of sepsis or multiple organisms are seen on the Gram stain or recovered in
culture, or if a large volume of free air is seen radiographically, a perforated viscus must be suspected, and appropriate
combination antibiotic therapy and surgical consultation are
indicated.
DIAGNOSIS
TREATMENT
Patients with PD-related peritonitis present clinically with
cloudy dialysate (98%), abdominal pain (79%) 479 and abdominal tenderness (70%), although frank rebound tenderness is
infrequent (50%). 486 In contrast to surgical peritonitis, PDrelated peritonitis is associated with fever only 53% of the
time . 479 Nausea and vomiting are common (25% of cases);
however, septic shock is unusual unless the infecting organism
is Staph. aureus.
Exit-site infection usually manifests with erythema and
crusting around the exit site. Frank purulence with fluctuance
over the subcutaneous portion of the catheter suggests tunnel
infection and is often associated with extrusion of the cuff.
The normal WBC in returned dialysate from uninfected
patients is <8 white cells/mm 3; in contrast, 90% of patients
with PD-related peritonitis will show a dialysate WBC
>100/mm3,497 many >500/mm3,498 associated with a neutrophilic predominance. However, up to 15% present with
monocytosis. 497 Delay in the rise of the dialysate WBC has
been reported 499 and therefore abdominal pain in a patient with
a PD catheter should be assessed with serial dialysate cell
counts and cultures to rule out PD-related peritonitis.
Lymphocytic pleocytosis may be the first clue to the presence
of an usual organism, such as Mycobacterium tuberculosis or
anomalous mycobacteria. Peritoneal eosinophilia has been
described with fungal infections 500 and hypersensitivity to
intraperitoneal antibiotics. 501
Gram-stain of centrifuged dialysate is positive in only
9-28% of cases 497,502 but when positive is useful for guiding
empiric antimicrobial therapy. Peripheral blood cultures are
usually negative and in the absence of signs of sepsis their value
is dubious. Whereas dialysate cultures are usually positive they
remain sterile in up to 30% of cases. Negative cultures are
Initial anti-infectioe therapy of PD-related peritonitis is based
on the most likely infecting organisms, namely Gram-positive
bacteria, unless the initial Gram-stain indicates to the contrary.
Since PD-related peritonitis is a local infection, treatment with
intraperitoneal antibiotics is preferred as very high levels are
achieved quickly, as are therapeutic blood levels, with most
antimicrobials.
Historically, concerns over infection caused by methicillinresistant organisms led to the use of vancomycin in empiric
regimens; however, the appearance of vancomycin resistance
among enterococci 5 o6 (and, even more alarmingly, among
Staph. aureus 507) has prompted recommendations to limit the
empiric use of this critical antibiotic. 508 Empiric regimens that
include a group 1 cephalosporin, either cephalotin or cefazolin,
or cefepime combined with an aminoglycoside have been
shown to be equivalent to vancomycin containing regimens, 509
and vancomycin can be withheld unless a patient has infection
caused by MRSA or has life-threatening allergy to R-lactam
drugs (Table 45.8). Studies of once-daily intraperitoneal
cephalosporin regimens have shown blood and intraperitoneal
drug levels far above the MIC of most infecting Gram-positive
organisms for the entire 24-h period, with therapeutic success
rates comparable to continuous administration of intraperitoneal cephalosporins. 510,511
Combined use of an aminoglycoside must take into account
the patient's residual renal function: patients with a urine
output >100 nil/day should not receive an aminoglycoside,
based on studies showing accelerated decline in renal function, 512 but should receive a higher dose of the R-lactam in
monotherapy; in contrast, patients with a urine output
<100 ml/day may safely receive a combined R-lactam/amino-
I NFECTIONS ASSOCIATED WITH PERITONEAL DIALYSIS CATHETERS
Table 45.8 Empiric antibiotic regimens for suspected peritoneal
dialysis related peritonitisa
Antibiotic
Daily dose
Residual urine output
<100 milday
>100 ml/day
Cefazolin or cephalotin
1 g/bag or
15 mg/kg/bagb
20 mg/kg/bag
Ceftazidime or cefepime
1 g/bagb
20 mg/kg/bag
Gentamicin, tobramycin, or
netilmicin
0.6 mg/kg/bag
Not
recommended
Amikacin
2 mg/kg/bag
Not
recommended
Adapted from Keane et al, 2000. 508
b Coadministered with an aminoglycoside: gentamicin, tobramycin,
netilmicin, or amikacin.
a
glycoside regimen (Table 45.8). Clindamycin, vancomycin,
and ciprofloxacin are acceptable alternatives in patients with
R-lactam allergies. 508
When the Gram stain or culture confirms the presence of a
specific organism, therapy should be adapted to reflect the sensitivities of that organism (Table 45.9). Staph. aureus usually
responds to 21 days of therapy with an intraperitoneal group
1 cephalosporin; however, in 20-51% of cases this results in
catheter loss, 479,513 especially when there is a concurrent exit
site or tunnel infection (which results in loss of the catheter in
70-80% of episodes514,515 ). If symptoms of infection persist for
more than 72 h or a patient has experienced a recurrent bout
of peritonitis, rifampicin should be added. 508
Ps. aeruginosa infections are very difficult to treat and even
with combination antimicrobial therapy have been associated
with failure rates and catheter loss ranging from 20% to
80%.516,517 Initial therapy requires two drugs, such as ceftazidime, cefepime or an antipseudomonal penicillin, in combination with an aminoglycoside or ciprofloxacin (Table 45:9).
If peritonitis fails to clear or recurs within 4 weeks of discontinuing therapy, removal of the PD catheter is usually necessary.
Management of fungal peritonitis also represents a formidable challenge to the clinician, and is associated with failure
rates approaching 35%, 518.519 despite therapy that includes
early removal of the PD catheter and prolonged antifungal
therapy. Fungal peritonitis has been associated with a mortality ranging from 17% to 32%. 520,521 A single retrospective study
reported a catheter salvage rate of 64% with the use of prolonged antifungal therapy, 515 although the number of cases was
small. Other, larger, case series have reported high rates of
catheter loss, in the range of 66-86%. 518,519,521 Fluconazole
combined with flucytosine is the anti-infective combination of
choice for peritonitis caused by C. albicans,479 which has been
implicated in >75% of cases of fungal peritonitis, 520 and is generally continued for 4-6 weeks. Amphotericin B exhibits
broader antifungal activity than the currently available azoles,
but does not penetrate the peritoneum well when given intravenously522 and is irritating when given by intraperitoneal
route. 523 However, its use is recommended in critically ill
patients, when definitive identification of the fungus is pending,
and in known infections with filamentous fungi, such as
Aspergillus, which are intrinsically resistant to fluconazole. 508
Patients with PD-related peritonitis should be instructed to
increase their dialysate dwell times as this is associated with
increased peritoneal levels of IgG and activated macrophages. 524 Some authors have recommended discontinuing PD
altogether for at least 48 h in an attempt to allow recovery of
a local inflammatory response to help control the infection. 525
Anecdotally, the use of thrombolytics has been reported to be
beneficia1 526 but at this time neither intervention can be routinely recommended.
The decision to remove the PD catheter must take into
account the patient's dialysis requirements, the availability of
vascular access if transitioning to hemodialysis, the type of
infection and, obviously, the patient's wishes. Fungal peritonitis, as noted, is associated with high mortality, 520,521 as is
peritonitis caused by Staph. aureus. 527 I n seriously ill patients
with peritonitis caused by these two organisms, a low threshold for early PD catheter removal is advisable. Additional indications for PD catheter removal include Ps. aeruginosa
peritonitis not responding to therapy, obvious tunnel or refractory exit site infection, fecal peritonitis, relapsing bouts of peritonitis with the same organism or recurrent bouts of
culture-negative peritonitis. 479 Several studies have demonstrated the utility of one-stage removal of the infected catheter
with simultaneous placement of a new PD catheter, 128,529 with
success rates as high as 83%. 529
PREVENTION
Given the dominance of catheter contamination in the pathogenesis of PD-related peritonitis, interventions aimed at reducing microbial colonization of the extraluminal and intraluminal
surfaces of the PD catheter would seem most likely to impact
favorably on the risk of infection. The first effective technologic innovation was the Y-set connector system, which
reduces the number of times that patients must access their
PD catheter by allowing simultaneous connection of the
drainage and infusion bag. 530 This initial single bag system,
which only comes with an attached drainage bag, to which the
patient must connect a fresh dialysate bag, also allows for a
` flush before fill' technique whereby micro-organisms that may
have gained intraluminal access during the initial connection
of the dialysate bag to the connector are flushed from the
catheter into the drainage bag, after which the peritoneum is
emptied, then refilled with fresh dialysate. Randomized trials
have shown a reduction in the rate of PD-related peritonitis
from one episode per 7.5-11 patient-months with standard
delivery systems to 1 episode per 15-43 patient-months with
Y-delivery systems. 487-489,531
Newer twin-bag systems that come pre-attached with both
I
60 5
606
I CHAPTER 45
I NFECTIONS ASSOCIATED WITH IMPLANTED MEDICAL DEVICES
Table 45.9 Recommended regimens for specific organisms causing peritoneal dialysis-related peritonitisa
I nfecting organism i nitial antibiotics
At 48-96 h
Duration of
therapy
Enterococci
Ampicillin 125 mg/I/bag combined with an aminoglycosideb
or
Vancomycinc 15-30 mg/kg i.v. every 5-7d
If no improvement, reculture and evaluate for a
concurrent exit site or tunnel infection
14 days
Staphylococcus
Group 1 cephalosporin
or
Vancomycinc 15-30 mg/kg i.v. every 5-7d
Start rifampicin 600 mg/day orally. If no
i mprovement, reculture and evaluate for a
concurrent exit site or tunnel infection
21 days
Coagulase-negative
staphylococci
Continue cephalosporin
14 days
Pseudomonas spp.
Ceftazidime or cefepime 1 g/bag daily plus an
aminoglycosideb if U0<1 00 ml/day
Ciprofloxacin 500 mg p.o. twice daily if UO>100 ml/day
or
Piperacillin 4 g i.v. every 12 h plus an aminoglycosideb if
UO<100 ml/day.
Ciprofloxacin 500 mg p.o. twice daily if UO>l00 ml/day
or
Aztreonam 1 g/I load followed by 250 mg/I/bag plus
an aminoglycosideb if UO<100 ml/day.
Ciprofloxacin 500 mg p.o. twice daily if UO>100 ml/day
Consider vancomycin if methicillin resistance
documented. If no improvement, reculture and
evaluate for a concurrent exit site or tunnel infection
If no improvement, reculture and evaluate for a
concurrent exit site or tunnel infection. Consider
removal of peritoneal dialysis catheter
Stenotrophomonas
spp.
Trimeth roprim-sulfamethoxasole 1-2 IDS tabs/day ±
ciprofloxacin 500 mg p.o. twice daily (confirm sensitivities)
Consider removal of dialysis catheter
21 days
Other Gram-negative Aminoglycosideb if UO<100 ml/day
bacilli
Ceftazidime 1 g/bag daily if UO>100 ml/day
If no improvement, reculture and evaluate for a
concurrent exit site or tunnel infection
1 4 days
Fungi
Remove PD catheter and start fluconazole 200 mg p.o.
or i.p. qd plus flucytosine 1 g p.o. qd
Amphotericin 8 if resistant yeast or filamentous,fungi
are present or the patient is severely ill
If dialysis catheter retained it should be removed
at 48 hours if infection not clearing
4-6 weeks
Culture-negative
Continue cepahlosporin and stop aminoglycoside,
if given with empiric regimen
Reculture fluid if patient not improving and adjust
based on results. Consider infection with fungi and
mycobacteria
1 4 days
aureus
21 days
UO, urine output; i.p., intraperitoneally; p.o., by mouth; DS, double strength.
a Adapted from Keane et al, 2000 508
b Refer to Table 45.13 for dosing.
I Use only with confirmed ampicillin or methicillin resistance or in patients with major penicillin allergy.
a drainage and new infusion bag have demonstrated even lower
rates of infection than single bag systems, with rates of PDrelated peritonitis ranging from one episode per 12-14 patientmonths for the single bag system to one episode per 25-46
patient-months for the dual bag system. 532,533 Use of these
systems has resulted in a reduction in cases of Coagulase-negative staphylococcal peritonitis but has had little impact on
rates of Staph. aureus infection. 534 Given the predominance of
Coagulase-negative staphylococci in PD-related peritonitis,
wider use of Y-systems should result in significant declines in
rates of PD-related infection.
The use of CCPD, which requires only a single night-time
connection, also reduces the number of times a PD catheter
must be handled, and several studies have reported lower rates
of infection than in CAPD, which requires the PD catheter to
be accessed 3-4 times a day (one episode per 8-14 patientmonths in CAPD patients; one per 20-25 patient-months in
patients using CCPD 482,491 ).
Reducing rates of PD catheter exit site infections should, in
theory, also reduce the rate of PD-related peritonitis. Patients
with nasal colonization by Staph. aureus are much more likely
to develop PD catheter exit site infections 492,493,513,535,536 and
at least two studies have demonstrated that these patients are
also at increased risk of peritonitis.
A randomized clinical trial of oral rifampicin, 600 mg/day for 5 days every 3
months, regardless of Staph. aureus colonization, demonstrated
a significant reduction in the rate of Staph. aureus exit-site
infection. 537 Studies of the application of 2% nasal mupirocin
'3',536
I NFECTIONS ASSOCIATED WITH PERITONEAL DIALYSIS CATHETERS
ointment to the anterior nares, 2-3 times daily for 5 days each
month, have also shown reduced rates of PD catheter exit site
infection but no effect on rates of peritonitis; 538-140 moreover,
re-colonization by Staph. aureus occurred in the majority of
patients after 1 year. 54o Direct application of 2% mupirocin
ointment to intravascular catheter access sites has been shown
to reduce rates of IVD-related bloodstream infections in
patients undergoing hemodialysis, 54 I and studies of direct
application to PD catheter exit-sites has similarly shown a
reduction in CAPD exit-site infections. 142 However, these
studies did not show any favorable cost-benefit with mupirocin
use, 543 and sharply rising mupirocin resistance in Staph. epidermidis333 and Staph. aureus 544 clinical isolates have been seen
with routine use. We believe further studies are needed before
prophylactic mupirocin can be routinely recommended in PD
or hemodialysis.
Use of perioperative antibiotics for placement of permanent
PD catheters has recently been studied. 541,146 Rates of peritonitis occurring within 10 days of catheter placement were
lower in patients given perioperative cefuroxime compared to
placebo in one randomized trial; 545 another study demonstrated a reduced rate of PD-related peritonitis within 2 weeks
of the procedure with prophylactic use of either vancomycin
or cefazolin. 546
14.
15.
1 6.
17.
18.
1 9.
20.
21.
22.
23.
24.
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