Future Diagnostic

and Therapeutic
Approaches in
Surgical I nfe c tions
Barbara Haas, MDa,b,*, Avery B. Nathens, MD, PhD, MPHa,b
KEYWORDS
 Surgical infections  Microbiology  Antibiotics  Vaccines

Infections in surgical patients remain a significant cause of morbidity and mortality

despite advances made in source control, antimicrobial therapy, and adjunctive
therapies. Although there is much focus on optimizing the use of currently available
therapy and the translation of evidence into practice,15 there are a wide variety of
innovations that might prove to be critical assets in the battle between microbes
and their human host.
These innovations come at a critical time. The ability to support acute organ failure
through advances in critical care or chronic organ failure through transplantation and
immunosuppression is being challenged by the threat of increasing antimicrobial
resistance. As a result, many have emphasized the urgent need for novel strategies
either to prevent or treat infections caused by multidrug-resistant organisms.610
A number of diagnostic and therapeutic modalities currently in experimental phases
of development have the potential not only to improve patient outcomes, but also to
provide novel approaches to bypassing microbial resistance mechanisms, and represent potentially sustainable strategies in slowing the current rate of antimicrobial resistance. These innovative approaches include new and rapid diagnostic tests that could
limit exposure to broad-spectrum antimicrobials through quicker diagnosis and more
timely de-escalation; novel microbial targets to reduce pathogenicity; vaccine
approaches to infection prevention; and prognostic markers to identify those at
highest risk.

Department of Surgery, University of Toronto, 100 College Street, Toronto, Ontario, M5G 1L5,
Canada
b
Division of General Surgery, St. Michaels Hospital, 30 Bond Street, Toronto, Ontario, M5B
1W8, Canada
* Corresponding author. St. Michaels Hospital, Queen Wing, 3N-073, 30 Bond Street, Toronto,
Ontario M5B 1W8, Canada.
E-mail address: barbara.haas@utoronto.ca (B. Haas).
Surg Clin N Am 89 (2009) 539554
doi:10.1016/j.suc.2008.09.013
surgical.theclinics.com
0039-6109/08/$ see front matter 2009 Elsevier Inc. All rights reserved.

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NOVEL APPROACHES TO DIAGNOSTIC ASSESSMENT

Antibiotic exposure is the principal driving force behind emerging resistance.6 Many
antimicrobial guidelines emphasize the need to avoid the use of antimicrobials in clinical settings where they are unlikely to be of benefit, to narrow the spectrum when possible, and to reduce the duration of exposure.1113 These goals are counter to those
that might be in the best interest of the patient, as early empiric broad-spectrum therapy has been associated with a survival benefit.1416
The current approach to antimicrobial prescribing is in conflict with what might be
ideal practice because of currently used microbial diagnostics. Conventional culture
and microbial identification techniques typically require almost 72 hours for pathogens
to be identified, speciated, and susceptibility patterns established.8 During this time of
diagnostic uncertainty, the patient, particularly the critically ill patient, is treated with
broad-spectrum antibiotics, with de-escalation of therapy delayed until a definitive
diagnosis is made. Moreover, conventional cultures may not identify the offending
pathogen. This is particularly true of fastidious or slow-growing organisms, which
include not only unusual pathogens, but also many fungal pathogens and a number
of commonly encountered bacteria.17 In addition, cultures taken after the initiation
of antimicrobial therapy may have low yield, despite the presence of clinically important infection.18
The need to balance efforts to minimize the use of antimicrobials and to treat the
patient adequately during a period of diagnostic uncertainty has led to the development of novel diagnostic strategies for the detection of pathogenic organisms based
on advances in genomics and molecular biology.
Rapid Diagnostic Assessment

Traditionally, patient specimens are collected and then cultured in automated systems
that detect the presence of any bacterial or fungal growth. If a culture flags positive,
the pathogen is examined by means of Gram staining, which offers some diagnostic
clues as to the nature of the microorganism, and is then further cultured and examined
by various biochemical assays. Antibiotic susceptibilities are also examined during
this period. New diagnostic assays use a variety of molecular diagnostic techniques
to accelerate the diagnosis. The most common techniques include fluorescent in
situ hybridization (FISH), polymerase chain reaction (PCR) amplification of unique
genetic sequences, and microarray-based technology.
FISH relies on the use of a suspension of molecular probes that bind to a marker
specific to a particular pathogen (eg, a highly specific ribosomal RNA). The probes
have a detection system comprised of fluorescent markers that can be visualized
by microscopy. PCR relies on the exponential amplification of microbial genetic
material through an automated system; only a particular segment of genetic information is targeted by the assay, which ensures that if no pathogen with the genetic
sequence is present in the sample, no amplification occurs. The amplified product
is then detected, either directly or indirectly, through the presence of an automated
detection system. Finally, microarray technology refers to the practice of fixing a large
number of highly specific probes onto a stable medium, thereby enabling analysis of
a large number of DNA or RNA sequences in an automated fashion. Each of these
techniques has a large number of variations, and they are frequently used in tandem.
Culture-Based Assays

The majority of newer diagnostic assays use specimens derived from microbial
cultures after specimen collection, as opposed to immediae analysis of specimens

Future Diagnostic and Therapeutic Approaches

obtained from the patient. Identifying pathogens from culture-positive specimens has
a number of potential advantages. It ensures that only cultures with live bacteria result
in a positive test. It also ensures that the appropriate molecular probes are used
through preliminary information obtained through Gram staining and early culture.19
An excess number of probes in a single reaction can lead to a greater chance of
a false-positive assay, and the information obtained through Gram staining and culture
can help tailor the choice of probes, limit costs, and increase the chance of a valid
result.
A wide range of assays aiming to identify pathogens from positive blood cultures
have been designed. Although some are designed to detect only one or two specific
pathogens, many have been developed to assess for the presence of a wide spectrum
of organisms. As an example of the diagnostic utility of some of these assays, Oliveira
and coworkers20 developed a FISH assay to detect Staphylococcus aureus from
a positive blood culture specimen. Results diverged from conventional culture results
in less than 1% of cases, and results were available within 2.5 hours of a positive
culture. Marlowe and coworkers21 described a DNA probe matrix designed to identify
a variety of gram-positive, gram-negative, and fungal pathogens within 1 hour of positive culture. The assay demonstrated less than 2% discordance with conventional
cultures.
There is considerable variability, however, in accuracy across the reported studies.
For example, a FISH assay designed to detect a wide range of pathogens identified
species in only 81% of cases with positive conventional cultures. This loss of sensitivity was caused by an inadequate breadth of gram-negative probes, illustrating some
of the inherent limitations of the high specificity of molecular diagnostic techniques.22
Specifically, there must be a probe present for all potential organisms. Other assays
designed to detect a wide range of pathogens, by FISH or amplification methods,
have reported similar difficulties in identifying all clinically encountered pathogens to
the species level.2326 These assays are not quite ready for widespread use in the
clinical setting.
Other Uses for Molecular Diagnostic Strategies

There are several other potential applications for molecular diagnostic strategies that
might prove valuable in the future. In part, these applications provide greater hope for
success because they focus on particular organisms or clinical problems rather than
casting a wide diagnostic net. For example, molecular diagnostic assays have proved
to be useful in the rapid detection of antibiotic resistance genes. Several assays have
been developed that can detect the presence of multiple genes concurrently in
a matter of hours.2731 One study examined an oligonucleotide microarray that could,
through PCR amplification, detect 90 different antibiotic resistance genes in grampositive bacteria.32 Another assay used microarray analysis to detect 61 different
resistance genes from different species of bacteria, and to identify instances of horizontal gene transfer.33 Nevertheless, the practical limitation of this approach is the
constant evolution of new resistance genes, or their transfer to new pathogens, which
requires a continuous updating of available assays.
Where the molecular diagnostic approach does seem to offer an advantage is in the
rapid detection of methicillin-resistant S aureus (MRSA), a phenotype generally conferred by the mecA gene in S aureus.34 S aureus is the most common blood-borne
pathogen and the most important pathogen in the postoperative period.35,36 Further,
the increasing prevalence of MRSA has altered the approach to both prevention and
treatment of suspected infections caused by S aureus.36,37 New diagnostic assays
might simplify the approach to the identification and treatment of staphylococcal

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infections. For example, the preliminary Gram stain of a blood culture result might be
gram-positive cocci in clusters. Most commonly, this result might represent a clinically insignificant contaminant with coagulase-negative staphylococci, or a bacteremia caused by methicillin-sensitive S aureus or MRSA. Several groups have
developed PCR and microarray-based assays that discriminate between S aureus
and coagulase-negative staphylococci with 100% reliability within hours of a positive
culture.3841 More importantly, although genomic analysis does not always correlate
precisely with phenotypic resistance patterns, multiple groups have described PCRbased assays with an accuracy of greater than 95% for the detection of MRSA in
mixed cultures.39,4244
The clinical utility of rapid diagnosis of S aureus bacteremia and identification of
MRSA has been demonstrated in a number of studies. In a retrospective study where
PCR was performed on specimens derived from patients with a positive conventional
blood culture, the PCR result, if available, would have better directed therapy in
a significant proportion of patients through a significant reduction in the use of vancomycin.39 In other studies comparing conventional and molecular diagnostic methods,
rapid results regarding MRSA status would have changed therapy in over 25%
of patients.42,45 PCR detection of MRSA directly from patients specimens has not
only been shown to decrease MRSA infection rates, but has been shown to be
cost-effective in the clinical setting.46
Like MRSA detection, postoperative fungemia represents another clinical domain in
which new diagnostic techniques could prove to be invaluable. Fungal organisms are
frequently difficult to detect and are associated with significant morbidity and mortality. Further, it might take as long as 4 to 5 days to reliably declare a blood culture negative for fungal pathogens. Novel diagnostic strategies using PCR or FISH have shown
tremendous promise in the rapid detection of these pathogens.4755 For example, Lau
and coworkers56 reported a PCR-based assay capable of detecting 11 species of
fungus from positive blood cultures. This assay correctly identified all cultures that
contained pathogens targeted by the assay with great accuracy in as little as 4 hours.
Another assay using FISH to detect Candida albicans from positive blood cultures
even demonstrated improved sensitivity compared with conventional methods.57
These fungal assays vary considerably in their complexity and costs, but many are
likely to be cost-effective given the changing face of fungal infections. The widespread
use of fluconazole has been associated with the emergence of resistant fungi including non-albicans Candida and non-fumigatus Aspergillus.8 As a result, caspofungin or
other more costly antifungals might be required as empiric therapy in certain clinical
settings.58 Rapid detection systems for fungal pathogens might allow for more rapid
de-escalation and overall cost savings.59,60
Specimen-Based Assays

The primary disadvantage of the previously described molecular diagnostic techniques is their reliance on a period of in vitro culture of the organism. With the advent
of newer diagnostic techniques that might directly detect pathogens in specimens
without the need for prior culture, there is the potential for further reducing the time
to diagnosis. PCR-based assays designed to detect S aureus and Enterococcus
faecalis directly from blood samples have been developed.61 Of greater use might
be a recently described multiplex PCR assay that detects the presence of multiple
gram-negative, gram-positive, and fungal organisms in blood samples, and which
provides results within 7 hours of specimen collection.62,63 Most specimen-based assays have sensitivities in the range of 65% to 75%, however, particularly with clinical
specimens, too low to be of clinical use.6164 This lower sensitivity is likely caused by

Future Diagnostic and Therapeutic Approaches

the presence of other compounds that interfere with the sensitive reactions on which
these diagnostic tests rely. Although these assays hold promise, there are significant
technical limitations that need to be overcome.
Pathogen Profiling

In addition to providing conventional information faster, molecular diagnostics are

improving to the point that they will soon provide a new class of diagnostic information. Specifically, it will likely be possible to generate a more comprehensive, genetically based profile of the organism to better estimate the potential for pathogenicity or
contribution to the clinical picture. This pathogen profiling provides information
regarding the organism of interest, including the presence of resistance genes and
virulence factors, and acknowledges the tremendous within-species and temporal
variability in gene expression.65 With the data accruing over time, this information
could be linked to the probability of a clinically relevant phenotypic behavior and could
be used to guide clinical decision-making. This approach would provide not only information about the pathogens present phenotype (potentially in a more timely manner),
but also might provide insight into the likely future behavior of the pathogen in vivo. For
example, pathogen profiling has been used to guide use, dose, and duration of antiviral therapy in the context of hepatitis C infection.65 Pathogen profiling has also been
applied to the evaluation of a wide range of pathogens, including Escherichia coli,
Pseudomonas aeruginosa, and S aureus strains, and to their virulence factors.66,67
With further experience it might soon be possible to determine whether an organism
is a colonizer or a pathogen and its propensity for the development of antimicrobial
resistance. The rapid transmission of this information to the clinician might have direct
impact on the approach to any identified organism.
NOVEL APPROACHES TO THERAPEUTICS

The discovery of effective and relatively nontoxic antimicrobial agents from environmental sources has historically led to a focus on natural sources of new antibacterial
and antifungal agents.68 Few antimicrobials are purely synthetic in origin, and potential
antimicrobials are typically identified by screening candidate compounds against live
pathogens. Compounds identified by this method target molecular processes
required by the organism for survival or for propagation. By definition, this approach
has led to antimicrobials that stimulate bacterial evolution by making high mutation
rates more adaptive, and leads to resistance.69,70
A proposed alternative is the targeting of so-called virulence factors, bacterial
products that play a causal role in the manifestations of disease either by enabling
the steps that lead to infection, or by causing disease symptoms (eg, secreted
toxins),69,71 but which are not essential to the pathogens survival. It is thought that
such antimicrobials, which may cause less selection pressure, would be less likely
to lead to the rapid emergence of resistance.69
Although antimicrobial strategies targeted at virulence factors are as varied as the
potential mechanisms of virulence, the greatest future success might lie in targeting
bacterial quorum-sensing pathways. Quorum-sensing, which is the mechanism by
which bacterial populations modify their gene expression in response to changes in
the density of surrounding organisms, is closely linked to pathogenic behavior in
many bacterial species. This behavior includes host invasion; surface adhesion; intercellular signaling; evasion of host defenses; and modification of the host environment
(eg, toxins).71,72 This strategy holds tremendous promise for therapy and might also

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play an important role in limiting the surface adhesion and biofilm formation that is
a necessary first step in infections of surgical implants.
Quorum-sensing seems to be so critical to bacterial pathogenicity that therapies
against this target may be highly effective. For example, inhibition of the quorumsensing cascade in a murine model of S aureus infection blocked abscess formation.
Further, this effect was evident with only transient blockade of the quorum-sensing cascade in the earliest phases of infection.73 RNAIII-inhibiting peptide (RIP), which inhibits
quorum-sensing in S aureus without decreasing bacterial cell counts, has been found to
be potentially useful in a number of models. When administered as an antibiotic lock
therapy to animals in a model of catheter-related bacteremia, catheter colonization
was reduced after injection of S aureus directly into the catheter, and completely eliminated when RIP was used in combination with antibiotics.74 In a murine model of polyethylene terephthalate (Dacron) graft infection, presoaking the graft with RIP decreased
the growth of S aureus by a thousand-fold.75,76 Further, a compound that is a nonpeptide analogue of RIP, and occurs naturally in the bark of witch hazel, interfered with
bacterial adhesion and biofilm formation in an in vitro model, and demonstrated
a dose-dependent inhibition of graft colonization in a murine model.77 Finally, quorum-sensing has been targeted through the generation of monoclonal antibodies
against AIP-4, which is involved in the quorum-sensing system of S aureus. Passive
immunization with these antibodies resulted in increased survival in a murine model of
S aureus intraperitoneal sepsis.78
Quorum-sensing mechanisms have also been well documented and extensively
studied in another common hospital-acquired pathogen, P aeruginosa. It has been
demonstrated, for example, that azithromycin interferes in quorum-sensing pathways
of P aeruginosa, and may be potentially beneficial in patient populations susceptible to
chronic infections by this pathogen.79 The therapeutic potential of targeting quorumsensing is also evident in another experimental approach, involving immunization
against a pseudomonal autoinducer. This increased survival in a murine model of
P aeruginosa pulmonary infection, but resulted in no change in bacterial cell counts.80
This suggests that the observed decrease in mortality was caused by prevention of
bacterial pathogenicity, rather than by growth inhibition. Targeting quorum-sensing
pathways is not universally beneficial, however, and there seems to be dose-related
effects that might even be harmful. The complex nature of quorum-sensing has
been highlighted in this species in experiments demonstrating that subtherapeutic
doses of other common agents, such as tetracycline, tobramycin, and ciprofloxacin,
paradoxically induced genes associated with biofilm formation, and that subtherapeutic doses of tobramycin promote motility.81,82
Based on evidence to date, therapies targeted at bacterial virulence factors potentially offer a highly attractive combination: decreased pathogenicity without interference in cell replication, and a decreased likelihood of creating a strong selective
pressure for resistance. Although the described therapies have not been evaluated
in clinical trials, therapies aimed at virulence factors may be highly promising novel
antimicrobials.
INFECTION PREVENTION THROUGH VACCINATION

Vaccines have likely been, historically, the most effective medical intervention for the
prevention of infection. The advent of pathogen profiling and a broader understanding
of the relationship between organism and host have led to a more sophisticated
approach to vaccine development. Many of the pathogens commonly seen in surgical
practice, such as S aureus and group A streptococci (GAS), have not been, until

Future Diagnostic and Therapeutic Approaches

recently, preventable through vaccine strategies. A major obstacle in the development

of effective vaccines against these pathogens is the high degree of variability of their
surface antigens. The large number of resultant serotypes, the number of which is
further increased by bacterial phase variation, makes creating a vaccine that results
in universal resistance against the pathogen challenging.83,84
There are efforts underway to develop vaccines effective in preventing infections
caused by S aureus given the burden of disease caused by this organism. Animal
experiments and clinical trials have met with mixed results. A vaccine based on the
S aureus capsular polysaccharide types 5 and 8, which account for 93% of clinical isolates, was evaluated in a large cohort of patients with end-stage renal disease.85,86
The vaccine did not reduce the incidence of S aureus bacteremia over the year of
observation; however, additional analyses suggest that periodic boosters might
improve the vaccines efficacy.
In a more recent study, animals were vaccinated with a nontoxic peptide similar in
structure to alpha hemolysin, a cytotoxin produced by S aureus, which resulted in the
production of an antibody directed against the active peptide. This antibody proved
protective in a murine model of S aureus pneumonia.87 S aureus quorum-sensing
has also been used as a vaccine target. For example, immunization against a bacterial
product involved in staphylococcal quorum-sensing resulted in increased survival in
a murine model of intraperitoneal S aureus sepsis.88
GAS is a highly virulent organism, and like S aureus is of considerable surgical
importance given its role in severe skin and soft tissue infections. As a result, many
investigators have focused on developing effective vaccines directed against this
organism or its virulence factors. The M protein of GAS, of which there are at least
100 variants, is responsible for specific immunity against this pathogen. In addition,
antibodies directed against the M protein cross-react with certain human antigens.
Taken together, these two factors significantly complicate the development of
a safe and effective vaccine.89,90 Recent analyses, however, have identified regions
of the M protein that are both highly antigenic and specific to GAS. This has resulted
in the construction of a polyvalent vaccine that has undergone phase I studies in
humans.90 It is estimated the vaccine could prevent up to 50% cases of invasive
disease in adults, and an equal proportion of GAS-related deaths.89
Some of the challenges associated with identifying a universal vaccine target for
species with highly variable antigens have recently been simplified with novel genomics-based approaches. Reverse vaccinology refers to the process of screening
genomic sequences for regions that are likely to represent potential vaccine targets,
such as cell membrane proteins that are conserved across species subtypes.83 This
approach has been used to identify potential vaccine targets for Streptococcus
pneumoniae,91 GAS,92 and Neisseria meningitidis.93,94 This approach has also been
used to create a potential S aureus vaccine, which in preliminary studies has been
demonstrated to provide protective immunity against S aureus from human clinical
isolates in a murine model.95
Another innovative methodology in vaccine development is the use of the so-called
antigenome approach to vaccine target identification.96 This approach uses antibodies collected from convalescent patients to screen antigen expression libraries.
In this way, only genes that produce antigens to which patients produce antibodies
are selected for further study. This limits the number of targets studied, and identifies
targets that are actually expressed in vivo. The antigenome strategy has, for example,
been successfully used in S aureus vaccine development where it has been proved
efficacious in murine models.97 More importantly, this vaccine generated a strong
immunologic response in primates despite pre-existing antibodies, suggesting that

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the vaccine could be used as a nosocomial vaccine. Similar approaches have been
used by other groups for S aureus and for S pneumoniae.96,98,99
Infection control through vaccination holds great promise. Although the described
therapies require many years of evaluation, a vaccine that might confer a moderate
degree of protection could have significant effects on the burden of disease without
the selection pressures associated with antimicrobial therapy. The challenge will
then be to target those at highest risk for infections, a daunting task given our relatively
primitive understanding of host-microbial interactions.
ADVANCES IN UNDERSTANDING HOST-MICROBIAL INTERACTIONS

The wide variation in outcomes following infection emphasizes the multiple factors
that play a role in dictating the hosts response to a microbial challenge. The hosts
response to infection might very well play a greater role in outcome than either the clinical context or the implicated pathogen. The observation that individuals differ in their
susceptibility to infection over and above the known clinical risk factors has been well
documented.100 Recent advances in high throughput genomics may allow identification of high-risk individuals by virtue of their genotypes. Specifically, several single
nucleotide polymorphisms, which represent minor genetic variations that occur in
a small proportion of the population, have been associated with adverse outcomes
related to infection.100,101
A systematic review of genes investigated for polymorphisms linked to the response
to infection identified 76 studies examining 51 different genetic polymorphisms.102
Genes investigated to date relate to those previously implicated in the host response
to infection, including genes associated with cytokine production, the coagulation
cascade, and signal transduction.103,104 As the associated technology becomes
increasingly rapid and affordable, however, it will likely become possible to scan the
genome for genes associated with susceptibility to infectious disease without prior
knowledge of their function.100
Polymorphisms related to tumor necrosis factor (TNF)-a and the Toll-like receptor
(TLR) family have been among the more extensively studied given the current understanding of the role of these proteins in the manifestations of infection. TNF-a is
a proinflammatory mediator that is produced in response to a wide range of stimuli,
and that has been implicated in a number of inflammatory diseases, including sepsis.101 The prevalence of the TNF2 polymorphism has been found to be significantly
higher among patients with septic shock than the general population,105,106 and has
been found to be an independent predictor of death among patients with septic
shock.105 Among surgical patients, TNF-a polymorphisms have been associated
with adverse outcomes among patients with postoperative septic shock.107
TNF-a polymorphisms have also been associated with surgical site or other nosocomial infections, suggesting it might be possible to identify those predisposed to
infection and to better target preventive measures. In a study of patients undergoing
esophagectomy, there was an association between TNF-a polymorphisms and
subsequent infection.108 The relationships are not simple, however, as the polymorphisms associated with infection in this study were found to confer protection in
others.105,106 Polymorphisms of the TNF-a gene have also been associated with
increased susceptibility to sepsis following severe burns and trauma.109111
Similar associations have been identified when polymorphisms pertaining to the
TLR receptor family have been evaluated. These receptors are key in recognizing
bacterial cell wall components and initiating the inflammatory cascade.112 The TLR4
mutation has been associated with increased susceptibility to gram-negative infection

Future Diagnostic and Therapeutic Approaches

among ICU patients113 and in patients with major burns.109 Others have demonstrated
an association between a polymorphism at the TLR2 gene and increased susceptibility to gram-positive and fungal infection among patients with septic shock.114,115
Although this line of investigation might yield promise in identifying those at highest
risk for infection, and those who might benefit from novel interventions, many of these
results are inconsistent across studies.108,116122 The inconsistent findings might be
caused by differences in methodology, small sample size, confounding through cosegregation of genetic loci, or gene interactions that are only poorly understood.100,102,112
It is anticipated that over time these investigations will yield considerable insights
into risk factors (and prognosis) related to infection. These association studies must
be performed using large populations of patients representing diverse ethnic and
racial backgrounds, however, to ensure the findings are generalizable to the population at large, and they must consider the complex interactions between genetic polymorphisms at multiple gene loci.103,123,124 If these methodologic issues can be
overcome, the clinical benefits would be tremendous. Additionally, these studies
would then allow for evaluation of new pathways that play a role in the development
or manifestations of infection, and provide new avenues of study for targeted interventions. These novel interventions would be directed against the host response or hostmicrobial interactions, and would not be encumbered by the adverse selection pressures associated with antimicrobial therapy.
SUMMARY

Innovations in the field of infection hold significant promise in the way surgical infections are prevented, diagnosed, and treated. Diagnostics will allow for more rapid
assessment of the causal pathogen and the likelihood of any particular organism
contributing to the manifestations of disease. Treatment strategies will focus not on
adding further selection pressures, but on compromising microbial virulence factors
to render them innocuous. We are still in the early phases of experimenting with vaccine strategies for infection prevention in this clinical setting, but newer techniques
might allow the development of effective vaccines for common nosocomial pathogens. Finally, the ability to identify patients at highest risk for infection through analyses of genetic polymorphism provides an opportunity to better understand hostmicrobial interactions and to target novel interventions.
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