Antimicrobial resistance among pathogens, such as Staphylococcus
aureus, coagulase-negative staphylococci, enterococci,
and aerobic gram-negative bacilli, is pervasive in the community
and hospital setting. Every practicing orthopaedist faces on a daily
basis the increasing problem of antimicrobial resistance in the
effort to prevent or treat nosocomial infections. Recognizing the scope
of the problem; understanding the mechanisms of antimicrobial resistance
as well as the epidemiology, prevention, and treatment of infections
due to resistant organisms; and knowing the proposed solutions to
these problems will optimize the orthopaedic surgeon’s ability
to manage multidrug-resistant nosocomial pathogens.
Vancomycin-Resistant Enterococci
Enterococci were classified as group-D streptococci until the
mid-1980s when nucleic acid studies showed that they were not genetically
related to streptococci36. Enterococci
are gram-positive aerobic cocci that are facultatively anaerobic
and can appear alone or in pairs and chains on gram stain37. They are easily identified by the clinical
microbiology laboratory. Currently, enterococci have their own genus,
Enterococcus, which contains twelve species. Two of them, Enterococcus
faecalis (80% to 90% of Enterococcus
infections) and Enterococcus faecium (5% to
10% of Enterococcus infections), are the most common species that
cause infection in humans. Enterococcus faecium is
most often associated with vancomycin resistance37.
Enterococci are normal flora of the human gastrointestinal tract,
but because they can survive in many environments they can also
be found in soil, food, and water37.
It is the ability of enterococci to survive for extended periods
of time in harsh environments that allows their easy dissemination
in the hospital when strict adherence to infection-control measures
such as hand-washing are not followed by health-care providers.
Enterococci are not as virulent as Staphylococcus aureus or
group-A streptococci. Their virulence lies in their intrinsic resistance
to the common antimicrobials (for example, cephalosporins) used in
hospitals today. Hospitalized patients may become colonized with enterococci
after exposure to these antimicrobials38.
Although enterococci cause a variety of both community-acquired
and nosocomial infections (for example, bacteremia, urinary tract
infection, infective endocarditis, and intra-abdominal infection),
osteomyelitis, septic arthritis, and infection around a prosthetic
joint are not commonly due to enterococci39-46.
Orthopaedists usually encounter these organisms in association with soft-tissue
or foot infections in patients with diabetes mellitus, peripheral
neuropathy, or vascular insufficiency41 (Table I). In this setting,
enterococci are often part of a polymicrobial infection.
Enterococci are intrinsically resistant to a number of antimicrobials, including
cephalosporins, clindamycin, antistaphylococcal penicillins, tetracyclines,
macrolides, and cotrimoxazole36-38.
Most enterococci have low-level resistance to penicillins. As such, penicillin
and vancomycin are bacteriostatic when used as monotherapy in susceptible
isolates. Aminoglycosides, such as gentamicin or streptomycin in
combination with penicillin or vancomycin, are useful because of
their in vitro synergism and are bactericidal for most
susceptible strains. Thus, for patients who require bactericidal therapy
to treat an enterococcal infection (for example, enterococcal infective
endocarditis), the treatment of choice historically has been penicillin
or vancomycin in combination with gentamicin or streptomycin37. Penicillin or vancomycin alone historically
has been standard therapy for other types of enterococcal infections.
In the last fifteen years, enterococci (usually Enterococcus
faecium) have acquired high-level resistance to penicillin
and aminoglycosides as well as to vancomycin. Typically, vancomycin-resistant
enterococci are also resistant to penicillin and aminoglycosides,
leaving the clinician with no approved antimicrobial therapy for
vancomycin-resistant enterococci (until the recent approval of linezolid
and quinupristin/dalfopristin)47-52.
Vancomycin-resistant enterococci were first reported in Europe
in 198636. Between 1989 and 1993,
the Centers for Disease Control and Prevention reported that vancomycin resistance
had increased from 0.3% to 7.9% of all enterococcal
isolates and from 0.4% to 13.6% of intensive-care-unit
enterococcal isolates in the United States53.
In 2000, the Centers for Disease Control reported that 24.7% of nosocomial
enterococcal infections in intensive care units in the United States
were vancomycin-resistant, a 40% increase compared with
the rate in the 1994-to-1998 time-period6.
Most patients are colonized (in the gastrointestinal tract), not
infected, with vancomycin-resistant enterococci. Vancomycin-resistant
enterococci, however, can and do cause types of infections similar
to those caused by vancomycin-susceptible strains. Investigators
have reported that the rate of mortality from bacteremia due to
vancomycin-resistant enterococci is higher than that associated
with vancomycin-sensitive strains, but whether this increase in mortality
is due to vancomycin resistance or to other factors remains controversial54-56. It is estimated that it costs
at least $25,000 more to treat an episode of vancomycin-resistant
bacteremia than it does to treat an episode of vancomycin-susceptible
bacteremia. Similar data are not available for osteomyelitis or
infection around prosthetic joints due to vancomycin-resistant enterococci57.
The factors believed to contribute to the acquisition of vancomycin-resistant
enterococci include exposure to antimicrobials, prolonged hospitalization,
an intensive-care-unit stay, proximity to a patient colonized or infected
with vancomycin-resistant enterococci, care by a nurse who is also
caring for a patient who is colonized or infected with vancomycin-resistant
enterococci, medical comorbidities such as renal failure, and hospitalization
in an institution that has a high proportion of patients who are
colonized with vancomycin-resistant enterococci36,58,59.
The role of exposure to vancomycin itself in the acquisition of
vancomycin-resistant enterococci is controversial in part because
of difficulties with the selection of controls and adjustments for
potential confounders in published studies60.
Thus, the prompt isolation of colonized patients and strict adherence to
infection-control policies are important for control of the nosocomial
spread of this microorganism61.
The emergence of vancomycin-resistant enterococci has raised concern
about the need to prevent organisms from becoming resistant to vancomycin.
Prevention of vancomycin resistance is important because of the
limited therapeutic options that are available and, probably more
importantly, because of the potential for transfer of genes for
vancomycin resistance from enterococci to other nosocomial pathogens
(for example, Staphylococcusaureus)9,62-64. Given the virulence of Staphylococcusaureus and
its prominence as the most common nosocomial pathogen, vancomycin-resistant Staphylococcus
aureus would be a major threat to public health.
The Centers for Disease Control presented recommendations for
preventing the spread of vancomycin resistance9.
These included guidelines concerning the prudent use of intravenous
and oral vancomycin. Particular points of interest to the orthopaedic
surgeon are shown in Table IV. It should be stressed that the guidelines
include a recommendation to limit perioperative prophylaxis with
vancomycin to a maximum of two doses for so-called clean orthopaedic
surgery involving the implantation of prosthetic material at institutions
with a high rate of superficial or deep surgical wound infections
due to methicillin-resistant staphylococci or in patients with severe
b-lactam allergies. Thus, the orthopaedist must have a close working
relationship with the infection-control officer and know the microbiological
characteristics of the orthopaedic surgical wound infections at
his or her hospital. In addition, a detailed allergy history and
targeted penicillin skin-testing may decrease the need to give vancomycin
to patients with a history of allergy to penicillin or cephalosporin65. Although the Centers for Disease Control
did not comment on the definition of a "high rate" of
infections due to methicillin-resistant staphylococci, an American
Academy of Orthopaedic Surgeons advisory statement indicated that
vancomycin may be appropriate as a prophylactic antimicrobial for
patients undergoing joint replacement at institutions that have
identified a substantial prevalence (for example, >10% to
20%) of methicillin-resistant Staphylococcus aureus and
coagulase-negative staphylococci among orthopaedic patients8. Cefazolin is still used as the standard
perioperative prophylactic agent for patients undergoing total joint
replacement at my institution66.
Vancomycin is also inappropriate for antimicrobial prophylaxis prior to
dental procedures in patients with a total joint replacement. An advisory
panel consisting of members of both the American Academy of Orthopaedic
Surgeons and the American Dental Association recommended the use
of clindamycin, not vancomycin, when a dentist or orthopaedist wants
antibiotic prophylaxis to be administered before a high-risk dental
procedure in a patient with a total joint replacement and an allergy
to penicillin67.
It should also be noted that the Centers for Disease Control
discouraged the use of vancomycin solution for topical application
or irrigation. Hanssen and I recently reviewed the utility of topical
antibiotic irrigation in total joint replacement66.
It is my opinion that the use of vancomycin-impregnated bone cement in
total joint replacement surgery and vancomycin-impregnated beads in
surgery for the treatment of osteomyelitis should be limited to patients
with an established infection rather than be employed as routine
prophylaxis against infection. This opinion was based on the finding
of gentamicin resistance in patients in Europe who had been managed
prophylactically with gentamicin-containing bone cement68.
The Centers for Disease Control also recommended education of hospital
staff with regard to the problem of vancomycin resistance, early
detection and prompt reporting of vancomycin-resistant enterococci
by the clinical microbiology laboratory, and implementation of appropriate
infection-control measures. The Centers for Disease Control did
not comment on which of the intervention strategies would be most
useful in altering the prescribing practices of physicians. The Centers
for Disease Control did recommend that use of vancomycin be monitored
through the hospital’s quality-improvement process or as part
of the drug-utilization review by the pharmacy and therapeutics committee
and the medical staff.
The Centers for Disease Control made the following recommendations
for dealing with hospitalized patients who are found to be colonized
or infected with vancomycin-resistant enterococci9.
Place the patient with a vancomycin-resistant enterococcal infection or
colonization in a private room or with other patients who have vancomycin-resistant
enterococci colonization.
Wear clean, nonsterile gloves when treating a patient with vancomycin-resistant
enterococci.
Wear a clean, nonsterile gown if substantial contact with a patient who
has vancomycin-resistant enterococci is anticipated or if contact
with stool or wound drainage is likely.
Remove the gloves and gown before leaving the patient’s
room and wash hands with an antiseptic soap or waterless antiseptic
agent.
Avoid contact with potentially contaminated environmental surfaces (such
as a doorknob or curtain) after glove and gown removal and hand-washing.
Restrict the use of routine medical instruments (such as a stethoscope or
blood pressure cuff) to a single patient or group of patients with vancomycin-resistant
enterococci.
Obtain a stool culture or rectal swab culture from roommates
of patients who are found to have vancomycin-resistant enterococci.
As the duration of gastrointestinal tract colonization with vancomycin-resistant
enterococci may be indefinite, each hospital must adopt a policy
for when and under what circumstances to remove a patient colonized
with vancomycin-resistant enterococci from isolation9. In addition, each hospital should implement
a system to promptly reinstitute isolation of a patient with vancomycin-resistant
enterococcal colonization when the patient is readmitted to the
hospital.
Staphylococci
Staphylococcus aureus has been recognized as
a major human pathogen since the 1880s69,70.
Staphylococci are gram-positive aerobic cocci that usually are seen in
clusters on gram stain. Staphylococcus aureus produces
microcapsules and surface proteins, some of which are being used
to create vaccines that may be employed to prevent infection71. Staphylococcusaureus is
one of the most virulent and common nosocomial pathogens, in part because
of its extensive ability to produce enzymes and toxins71,72. Staphylococcusaureus can
both colonize and infect humans. Colonization can occur at birth.
The major site of colonization is the anterior nares72. As many as 30% to 50% of
healthy adults are colonized, and 10% to 20% may
be persistently colonized. Colonization with Staphylococcus
aureus is a risk factor for subsequent Staphylococcusaureus infection73-75. Clinical infections caused by Staphylococcusaureus are
numerous and include some of the most common infections managed
by orthopaedic surgeons (Table I).
Coagulase-negative staphylococci include fifteen different species,
of which Staphylococcus epidermidis, Staphylococcus saprophyticus, and
increasingly Staphylococcus lugdunensis are major
pathogens in humans76-78. Coagulase-negative
staphylococci, of which Staphylococcus epidermidis is
the most numerous, are normal human skin flora. Most infections due
to coagulase-negative staphylococci are nosocomially acquired and
develop around an indwelling medical device (such as a joint prosthesis)
or as a complication of an invasive medical procedure (such as arthroscopy)
in part because of the ability of these organisms to produce a biofilm76,79,80. However, there are exceptions
to this rule, such as urinary tract infections due to Staphylococcus
saprophyticus in healthy young women.
Acquired antimicrobial resistance among staphylococci has been
a problem since the advent of penicillin and sulfonamides. Currently, approximately
90% of staphylococci produce b-lactamase and therefore
are penicillin resistant81,82 (Table V). Infections
with methicillin-resistant Staphylococcusaureus have
become increasingly common despite attempts to limit their spread
through strict infection-control practices6,76,81,82.
Between the time-period of 1994 to 1998 and the year 1999, the prevalence
of methicillin-resistant Staphylococcusaureus among
all intensive-care-unit isolates reported to the Centers for Disease
Control increased by 40%6.
Methicillin resistance among coagulase-negative staphylococci was
even more prevalent, although the number of intensive-care-unit isolates
with methicillin-resistant coagulase-negative staphylococci reported
to the Centers for Disease Control increased by only 4% during
that same time-period6.
Unfortunately, methicillin or oxacillin resistance confers cross-resistance
to all other b-lactam antimicrobials including cefazolin76,82. In addition, methicillin-resistant isolates
are often resistant to other antistaphylococcal agents, such as cotrimoxazole,
clindamycin, and fluoroquinolones, leaving vancomycin as the primary
and standard treatment option for serious methicillin-resistant
staphylococcal infections, such as osteomyelitis and infection around
a prosthetic joint. De novo rifampin resistance
is uncommon among methicillin-resistant staphylococci, but like
most, if not all, fluoroquinolones, this agent should not be used
as monotherapy against staphylococci because of the rapid emergence
of resistance during therapy76.
Use of rifampin in combination with other agents for the treatment of
bone and joint infections remains controversial because of a lack
of data showing superior efficacy with its use. Furthermore, rifampin
has gastrointestinal side effects and drug-drug interactions, which
make it difficult to use83-90.
The new antimicrobials, linezolid and quinupristin/dalfopristin,
also have in vitro activity against methicillin-resistant
staphylococci and resistance to them remains uncommon49,91. Their role in the treatment
of methicillin-resistant staphylococcal infections remains to be
determined.
In addition, it is important to point out that many methicillin-resistant isolates
are also resistant to aminoglycosides at the standard concentrations
used to predict in vivo activity for parenteral
administration. It remains unknown whether the high concentrations
of an aminoglycoside that can be achieved without nephrotoxicity
or ototoxicity by means of local delivery in antibiotic-impregnated
bone cement will be effective against these resistant strains or
will promote antibiotic resistance or an infection with otherwise
metabolically inactive strains92.
Vancomycin resistance among certain coagulase-negative staphylococci
has been recognized for some time, but it remains a rare clinical problem93-96. Unfortunately, Staphylococcusaureus with
intermediate resistance to vancomycin has recently been reported in
studies from Japan and the United States97-104.
The resistance is low level, is associated with clinical failures,
and typically has occurred in patients with methicillin-resistant Staphylococcusaureus infections
that have been treated with prolonged courses of parenteral vancomycin.
Although Staphylococcus aureus with intermediate
resistance to vancomycin remains a relatively rare problem, there
is a potential for a serious public health threat. Microbiology
laboratories are aware of appropriate methods to detect vancomycin
or other antimicrobial resistance105,
and the Centers for Disease Control and other organizations have presented
guidelines for the prevention of these infections7,8.
These guidelines include recommendations to improve antimicrobial
use and microbiology laboratory methods to detect strains of Staphylococcus
aureus with intermediate resistance to vancomycin as well
as information on how to obtain approval of investigational antimicrobial
agents through the Centers for Disease Control. In addition, methods
to prevent the nosocomial transmission of intermediately vancomycin-resistant Staphylococcus
aureus include immediate notification of the responsible
clinician by the microbiology laboratory; immediate notification
of the Centers for Disease Control and the appropriate state health
department; and implementation of specific isolation procedures,
including the use of dedicated health-care workers to work one-on-one
with infected patients. There is an urgent need for additional research
on novel strategies to prevent staphylococcal infections, including
decolonization with mupirocin to eliminate nasal colonization and
nosocomial staphylococcal infections, and on the development of
antistaphylococcal vaccines106-111.
Solutions to the Bacterial Resistance Issue
Many individuals and groups have proposed solutions to the global threat
of antimicrobial resistance1,3,5,10,12,13,15,18.
These proposals include the assurance of the use of appropriate
antimicrobials through a multidisciplinary approach; the institution
of antimicrobial-resistance surveillance programs; the implementation
of aggressive infection-control programs in hospitals; education
of physicians and paramedical staff; computer-based monitoring of
and feedback on the use of antimicrobial agents; professional review
of hospitals by oversight agencies, such as the Joint Commission
on Accreditation of Healthcare Organizations; increased funding for
clinical and basic research; and regulatory reform. The reader is referred
to the individual references for specific details. Common elements
in most recommendations include improved antimicrobial use (in humans,
animals, and the agriculture industry), education of the health-care
community regarding antimicrobial resistance, and improved infection-control
practices within hospitals. Achieving these goals will require financial resources;
individual, institutional, and governmental support; and improved
information services within the health-care industry.