Infection in the solid organ transplant recipient

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Infection in the solid organ transplant recipient

Author Jay A Fishman, MDSection Editor Peter F Weller, MD, FACPDeputy Editor Anna R Thorner, MD

Last literature review version 16.2:May 2008
This topic last updated: April 29, 2008 (More)

INTRODUCTION
Solid organ transplantation has increased worldwide since the first successful human kidney transplant was performed in 1954. As immunosuppressive agents and graft survival have improved, infection and malignancy have become the main barriers to disease-free survival after organ transplantation. As a result of the growing population of immunosuppressed patients with prolonged survival, an increased incidence and spectrum of opportunistic infections is observed [1-3].

Guidelines for the diagnosis and treatment of infection in transplant recipients have been developed [3] .The risks of infection and an overview of specific infections in the solid organ transplant recipient will be reviewed here. The pretransplant evaluation for solid organ and bone marrow transplant (BMT) recipients, prophylaxis of infections in solid organ transplantation, and an overview of infections following BMT are discussed separately. (See "Evaluation for infection before solid organ transplantation" and see "Evaluation for infection before hematopoietic cell transplantation" and see "Prophylaxis of infections in solid organ transplantation" and see "Overview of infections following hematopoietic cell transplantation").

GENERAL PRINCIPLES
When invasive infection occurs, early and specific diagnosis, and rapid and aggressive treatment of infection are essential to good clinical outcomes.Potential etiologies of infection in these patients are diverse, including common, community-acquired bacterial and viral diseases, and uncommon opportunistic infections of clinical significance only in immunocompromised hosts [1-3] . Pulmonary processes can progress rapidly and may constitute medical emergencies [1] . These include infections due to P. carinii/jiroveci, Nocardia asteroides, Aspergillus spp, Cryptococcus neoformans, CMV, VZV, influenza, respiratory syncytial virus (RSV), R. equi, and Legionella spp.

Inflammatory responses associated with microbial invasion are impaired by immunosuppressive therapy, which results in diminished symptoms and muted clinical and radiologic findings. As a result, infections are often advanced (ie, disseminated) at the time of clinical presentation. Serologic testing is not generally useful for the diagnosis of acute infection in the immunocompromised host since seroconversion is often delayed. Such assays may be used to assess risk (eg, for latent infections, distant exposures). Antigen-based tests (eg, enzyme linked immunosorbent assays [ELISA]) or nucleic acid-based molecular assays (eg, polymerase chain reaction [PCR]) are needed in this population.

Altered anatomy following transplant surgery may change the physical signs of infection. Diagnosis often requires anatomic data from imaging such as computed tomographic (CT) scans or magnetic resonance imaging (MRI). Tissue biopsies with histopathology and microbiology are often needed to make a specific microbiologic diagnosis in transplant recipients. Such clinical samples must be obtained early in the clinical course to enhance the chance for successful therapy, to minimize side effects of therapy, and before the patient's illness progresses to a point where such procedures can no longer be performed. The choice of antimicrobial regimens is often more complex than in other patients due to the urgency of therapy and the frequency of drug toxicities and drug interactions. Antimicrobial resistance is increased in immunocompromised hosts and should be considered in the choice of antimicrobial regimens.

Surgical intervention is often necessary to cure localized infections (ie, debridement); antimicrobial agents alone are frequently inadequate. Drug levels provide only crude means of monitoring immunosuppressive regimens and patients are often more or less immunosuppressed than anticipated. Side effects of these regimens are also common. For all of these reasons, the central focus must be on disease prevention including drug therapy and vaccination. This requires stratification of the risk for various infections. (See "Prophylaxis of infections in solid organ transplantation" and see "Immunizations in patients who are waiting for or have undergone solid organ transplantation").

RISK OF INFECTION FOLLOWING TRANSPLANTATION
The risk of infection in the organ transplant patient is determined by a semi-quantitative relationship between two factors: the epidemiologic exposures of the individual and the "net state of immunosuppression" which is a measure of all of the factors which contribute to the individual's susceptibility (or resistance) to infection [1-4] . (See "Evaluation for infection before solid organ transplantation").

Epidemiologic exposures
To adequately assess epidemiologic exposures, the clinician must take a detailed history of potential encounters with a variety of pathogens, even if the exposure was relatively remote. Latent pathogens are often activated in the setting of immune suppression. The epidemiologic exposures of importance to an individual will vary based upon the nature of the immune deficits. Most transplant patients have multiple deficits. Thus, bacterial and fungal pathogens are more important in the setting of neutropenia while viral (eg, cytomegalovirus [CMV]) and intracellular (eg, tuberculosis [TB]) infections are more common with T cell immune deficits. Strongyloides stercoralis may reactivate many years following transplantation [1] .

Community-acquired pathogens
The transplant recipient can have contact with a number of potential pathogens within the community. These organisms include common respiratory viruses (influenza, parainfluenza, respiratory syncytial [RSV] virus, adenovirus, and human metapneumovirus). In addition, common bacterial pathogens may include: Streptococcus pneumoniae, Mycoplasma, Legionella, Listeria monocytogenes and Salmonella.

Vaccinations for pneumococcus and influenza virus are useful but may have reduced efficacy in immunocompromised individuals. (See "Immunizations in patients who are waiting for or have undergone solid organ transplantation"). In the appropriate geographic regions, endemic fungi (Histoplasma capsulatum or Coccidioides immitis), and common environmental pathogens (eg, Cryptococcus neoformans, Aspergillus spp, Cryptosporidia spp) will be observed. Thus, while specific infectious exposures within the community will vary based upon such factors as geography and socioeconomic status, the general dictum that "common things occur commonly" applies to transplant recipients. However, the severity and duration of infection, and the frequency of multiple simultaneous processes are features that differentiate the transplant recipient from the normal host.

Reactivation of infections
Reactivated infection may be derived from the organ donor or the recipient. Common viral infections that frequently reactivate following transplantation include herpes simplex virus (HSV), CMV, varicella zoster virus (VZV, shingles), hepatitis B (HBV), and hepatitis C (HCV), papillomavirus, and BK polyomavirus. Some exposures may have occurred many years before transplantation including geographically restricted systemic mycoses (eg, histoplasmosis, coccidioidomycosis, blastomycosis), Mycobacterium tuberculosis, Strongyloides stercoralis, Leishmania spp, or Trypanosoma cruzi [4-7]. An important goal of the pretransplant evaluation is to identify such latent infections so as to develop a preventive strategy for each.

Nosocomial infections
Transplant recipients are vulnerable to nosocomial infections, especially in the early posttransplant (ie, post-surgical) period in patients with prolonged hospitalizations or who require mechanical ventilation.

Pathogens include:

• Legionella spp and other gram-negative bacilli such as Pseudomonas aeruginosa Gram-positive organisms, particularly antimicrobial resistant species such as vancomycin-resistant enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA)

• Fungi such as Aspergillus spp and nonalbicans or azole-resistant Candida species [8]

• Clostridium difficile colitis

• When the air, food, equipment, or potable water supply either in the hospital or the home are contaminated with pathogens such as Aspergillus spp, Legionella spp, or gram-negative bacilli, clusters of infection can be observed in time and/or space.


Donor-derived infections
Infections that are derived from donor organ tissues and activated in the recipient are among the most important exposures in transplantation. Some of these infections are latent, while others are the result of bad timing (unappreciated active infection in the donor at the time of transplantation).Organ donors are screened to avoid transmission of certain infections to transplant recipients (show table 1). Nonetheless, transmission of infection from donor to recipient may still occur (show table 2). The data supporting transmission of the individual infections are discussed separately in the appropriate topic reviews for each infection.Several types of infection merit special attention: bloodstream infection; inapparent infections that are accelerated by immunosuppression; and a number of specific infections.

Bloodstream infection
Some donors may have active infection at the time of procurement. Certain bloodstream infections (eg, staphylococci, pneumococcus, Candida, Salmonella, E. coli) may "stick" to anastomotic sites (vascular, urinary, biliary, tracheal), and produce fever, bacteremia, or mycotic aneurysms. Proof of adequate therapy for such infections must be established prior to accepting organs for transplantation.

Inapparent infections accelerated by immunosuppression
Other infections may be inapparent or unusual (eg, West Nile virus, leishmaniasis, rabies, lymphocytic choriomeningitis virus, Chagas disease, HIV, herpes simplex virus) and may cause clinical syndromes that are accelerated by immune suppression.

As an example, lymphocytic choriomeningitis virus infection (LCMV) occurred in 2003 and 2005 in two groups of recipients of solid organ transplants [3,9,10] . LCMV was identified in tissues in all organ transplants recipients from both investigations. The isolates from each investigation were identical to each other but distinct between the two outbreaks. In contrast, the common donors had no clinical or laboratory evidence of infection, although the donor from the 2005 cluster had a history of exposure to a pet hamster. Seven of eight transplant recipients died; one survivor was treated with ribavirin and decreasing doses of immunosuppressants. An epidemiologic investigation, using phylogenetic analysis of virus sequences, eventually traced the origin of these infections to an animal distribution center in Ohio [11] .

Three patients in Australia who received a kidney or liver from a single donor died of a febrile illness with associated encephalopathy four to six weeks after transplantation [12] . High-throughput RNA sequencing from the allografts of two of the patients revealed an arenavirus that is related to LCMV. These results were confirmed by immunohistochemical analysis of allograft tissue as well as IgM and IgG antiviral antibodies from the serum of the donor. In addition, PCR revealed the presence of the virus in the kidneys, liver, blood, and cerebrospinal fluid of the recipients. The donor had just returned home from a three-month visit to rural areas of the former Yugoslavia.

CMV and EBV
Viral infections such as cytomegalovirus (CMV) and Epstein-Barr virus (EBV) are associated with particular syndromes and morbidity in the immunocompromised population. The greatest risk for invasive infection is seen in recipients who are seronegative (immunologically naive) and receive infected grafts from seropositive donors (latent viral infection). This risk constitutes the rationale for anti-CMV prophylaxis in such patients. (See "Cytomegalovirus infection in renal transplant recipients" and see "Infectious complications in liver transplantation" and see "Cytomegalovirus infection in lung transplant recipients" and see "Viral load testing for cytomegalovirus in solid organ transplant recipients").

Tuberculosis and histoplasmosis
Late, latent infections including tuberculosis and histoplasmosis may activate many years after transplantation. Disseminated mycobacterial infection may be difficult to treat after transplantation because of interactions between the antimicrobial agents used to treat infection (eg, rifampin, streptomycin, isoniazid) and immunosuppressive drugs. However, early emergence of tuberculosis in recipients has been described after receiving organs from a donor with undiagnosed active infection [13] .

HIV, HTLV, and hepatitis viruses
In 2007, four recipients of organs from a single donor, who had died from trauma, were infected with both HIV and hepatitis C [14] . The donor had presumably been infected during the weeks prior to death since the antibody tests for these viruses were negative during the pretransplant donor screening. The likelihood of tissue donors having viremia due to hepatitis B, hepatitis C, HIV, and human T lymphotropic virus (HTLV) was evaluated in 11,391 tissue donors to five tissue banks in the United States [15]. The estimated probability of viremia at the time of donation that would be undetected by screening with current serologic methods (because of the window period for infection) was 1 in 34,000 for hepatitis B, 1 in 42,000 for hepatitis C, 1 in 55,000 for HIV, and 1 in 128,000 for HTLV.

The use of nucleic acid amplification testing, which shortens the window period, was estimated to reduce the probabilities of viremia to 1 in 100,000 for hepatitis B, 1 in 421,000 for hepatitis C, and 1 in 173,000 for HIV. However, no available assays can completely exclude the risk of infectious transmissions, especially in the limited time available for decreased donor screening prior to transplantation.

Net state of immunosuppression
The net state of immunosuppression is a complex function determined by the interaction of several factors [16-21] :Type, dose, duration, and temporal sequence of immunosuppressive therapies (show table 3)

• Underlying diseases or comorbid conditions
• Presence of devitalized tissues or fluid collections in the transplanted organ
• Invasive devices such as vascular access or urinary catheters, surgical drains, and ventricular assist devices Other host factors affecting immune function including neutropenia, hypogammaglobulinemia, and metabolic problems (eg, protein-calorie malnutrition, uremia, diabetes)
• Concomitant infection with immunomodulating viruses including, CMV, Epstein-Barr virus (EBV), human herpesvirus (HHV)-6 and -7, HBV, HCV.


The sum of any congenital, acquired, metabolic, operative, and transplant-related factors is the patient's "net state of immune suppression". More than one factor is usually present in each host. The identification and correction of any modifiable risk factor is essential for the prevention and treatment of infection.

TIMING OF INFECTION POSTTRANSPLANTATION
Immunosuppressive regimens vary between centers, with the organ transplanted, and the patient population. As an example, "induction" with polyclonal or monoclonal anti-T-lymphocyte antisera may be used for renal transplantation from deceased donors but not in living donor transplant recipients or in liver transplant recipients with hepatitis C infection.

At some centers, patients may receive little or no glucocorticoid therapy but are treated with combinations of multiple other potent immunosuppressants. Alterations in the type or intensity of immune suppression will alter the risk of infection (show table 3) and the list of potential pathogens (show table 2).It is useful to divide the posttransplant course into three time periods related to the risks of infection by specific pathogens: the early period posttransplant (up to six weeks); an intermediate period (one to six months); and more than six months (show figure 1) [1,3] .

This timetable is useful in three ways:

• In developing a differential diagnosis for the individual transplant recipient with clinical signs of infection
• As a clue to the presence of excessive environmental hazards (nosocomial, community or individual)
• As a guide to the design of preventive antimicrobial strategies

First month after transplantation
In the first month posttransplant, there are two major causes of infection in all forms of solid organ transplantation: infection derived from either the donor or recipient and infectious complications of the transplant surgery and hospitalization. The major effects of exogenous immunosuppression are not yet evident. Exceptions include those patients who receive suppression prior to transplantation (eg, for autoimmune hepatitis).

Donor-derived infections

The risk for infections acquired with the allograft have been discussed above (show table 2) [22] . Transmission of donor-derived bacteria and fungi have increased with the emergence of antimicrobial resistance such that vancomycin-resistant enterococci, methicillin-resistant staphylococci, and fluconazole-resistant Candida species may be transmitted from donor to recipient. Graft-associated viral infections (LCMV, West Nile virus, rabies, HIV) and parasitic infections (toxoplasmosis, Chagas disease), are uncommon, but may be amplified in the immunosuppressed host. Endemic infections (eg, histoplasmosis or tuberculosis) should be considered in the differential diagnosis of post-transplant infection or unusual clinical syndromes (eg, encephalitis, hepatitis).

Recurrent infection
Infection may have been present in the donor or in the recipient prior to transplantation. An important component of the pretransplant evaluation is to recognize and treat such infections, if possible. (See "Evaluation for infection before solid organ transplantation").Bacteria and fungi that have colonized the recipient or donor (eg, the lungs or sinuses in cystic fibrosis) are among the infections that may reactivate early. Donor-derived infections acquired pretransplantation while the patient is hospitalized awaiting surgery may include relatively resistant nosocomial pathogens (eg, vancomycin-resistant enterococcus) and pathogens such as Aspergillus spp that are resistant to usual prophylactic agents. In addition, some common viral infections (HBV, HCV, human immunodeficiency virus [HIV]) may reemerge early after transplantation [23] . Recipient-derived tuberculosis or toxoplasmosis tends to reactivate more than a month after transplantation. Reactivation of Strongyloides may be accompanied by gram-negative bacterial sepsis, meningitis, or pneumonia.

Infectious complications related to surgery
Solid organ transplant recipients develop many of the common postoperative complications, such as aspiration pneumonitis, surgical site infections, "line sepsis", urinary tract infection, or pulmonary embolus [24] . Transplant recipients are also at risk of superinfection of ischemic or injured graft tissues (eg, anastomotic suture lines), or of fluid collections (eg, hematomas, lymphoceles, pleural effusions, urinomas). These patients are at increased risk for infection associated with indwelling vascular access catheters, urinary catheters, and surgical drains. Patients receiving antimicrobial agents are at increased risk for C. difficile colitis. Patients at particular risk of nosocomial infection are those requiring prolonged ventilatory support or those with diminished lung function, persistent ascites, stents of the urinary tract or biliary ducts, with intravascular clot or ischemic graft tissue [20,25] . Individuals with delayed graft function or who require early reexploration or retransplantation are also at increased risk for infection, notably with fungi or bacteria with antimicrobial resistance.

One to six months after transplantation
In the period one to six months posttransplant, the nature of common infections changes. This is the period when patients are most at risk for the development of opportunistic infections although residual problems from the perioperative period can persist. There is significant geographic and institutional variation in the occurrence of opportunistic infections during the first six months posttransplantation. This reflects local epidemiology and varying immunosuppressive strategies and also the use of antimicrobial prophylaxis in the post-transplant period.

Major infections due to opportunistic pathogens include:Pneumocystis jiroveci/carinii pneumonia (PCP) Latent infections, such as the protozoal diseases including toxoplasmosis, leishmaniasis, and Chagas disease [4,18,19,26,27] The geographic or endemic fungal infections histoplasmosis, coccidioidomycosis, and rarely blastomycosis (show table 3) Viral pathogens, particularly the herpes group viruses but also HBV and HCV. New viruses are recognized as opportunistic pathogens with the use of more sensitive molecular assays (eg, BK polyomavirus, HHV-6, -7, and -8 [Kaposi's sarcoma-associated herpesvirus, KSHV]) (show table 4). Respiratory viruses are increasingly important in this population (influenza, parainfluenza, RSV, adenovirus). TB and, increasingly, non-tuberculous mycobacteria (NTM) [28] Gastrointestinal parasites (Cryptosporidium and Microsporidium) and viruses (CMV, rotavirus) may be associated with diarrhea

More than six months after transplantation
More than six months posttransplant, most patients are receiving stable and reduced levels of immunosuppression. These patients are subject to community-acquired pneumonias due to respiratory viruses, the pneumococcus, Legionella, or other common pathogens.In addition to community-acquired pathogens, rare infections may also occur in the late transplant period and may have clinical findings that differ from those in immunocompetent hosts. As an example, a prospective study of recipients of solid organ transplants (kidney, liver, and kidney-pancreas) in France revealed hepatitis E virus (HEV) as a late complication [29] . Acute HEV infection was recognized in 14 of 217 patients (6.5 percent), eight of whom developed apparent chronic HEV infection. A case of chronic HEV infection with rapid progression to cirrhosis in a kidney transplant recipient from France has also been described [30] . (See "Hepatitis E virus infection", section on After solid organ transplantation).

Late infection can occasionally be related to transmission from the transplanted organ and may be difficult to recognize as a result. Disseminated histoplasmosis has been reported in two seronegative renal transplant recipients who lived in different states where histoplasmosis is not endemic, eight and nine months after receiving organs from a single, seropositive donor [31] . Transplantation of the liver from this same donor into a third recipient did not result in histoplasmosis.

One renal transplant recipient developed widespread Kaposi's sarcoma and another developed bone marrow failure after receiving organs from an HHV-8 seropositive donor [32] .Patients who have less satisfactory graft function may require more intensive immunosuppressive therapies. These individuals are termed "chronic n'er do wells" and represent the subgroup of transplant patients at highest risk for opportunistic infections including PCP, cryptococcosis, or nocardiosis. They are also at risk for more severe community-acquired infections due to influenza or L. monocytogenes. Prolonged antimicrobial prophylaxis may be indicated for this subgroup of patients, who remain more immunosuppressed.

VIRUSES AS COPATHOGENS
Viruses, particularly CMV, serve as an important cofactor to many opportunistic infections [1,2,16,17,33] . The potential effects of viral infection are diverse and apply not only to CMV but also to HBV, HCV, EBV, and probably other common viruses such as RSV, HHV-6, and adenovirus (show table 4 and show table 5). Viruses contribute to a variety of processes post-transplantation [1,17,20,34-36] .

Direct effects
"Direct effects" include clinical syndromes such as fever and neutropenia (CMV), pneumonitis (respiratory viruses), hepatitis (HCV, HBV), gastritis, esophagitis, colitis (CMV), cholangitis (VZV), encephalitis (HSV, JC virus), pancreatitis, myocarditis, and retinitis. Less common syndromes include adrenalitis with adrenal insufficiency or meningoencephalitis due to CMV vasculitis.

Indirect effects
"Indirect effects" are generally immune effects including:Immune suppression and predisposition to opportunistic infection (eg, Aspergillus after RSV pneumonia, Pneumocystis after CMV infection). Thus, CMV coinfection has been implicated in the accelerated course of HCV infection with cirrhosis and graft loss, and of EBV with increased risk for post-transplant lymphoproliferative disorder (PTLD, usually B-cell lymphoma). Graft rejection that is thought to be mediated by proinflammatory cytokine release and/or upregulation of histocompatibility antigens or adhesion proteins [34,37,38] . Graft rejection may necessitate an increase in the immunosuppressive regimen and an increased risk for opportunistic infection Oncogenesis: Many viruses predispose to cancer (HCV, EBV) or to cellular proliferation (CMV and accelerated atherogenesis, BK polyomavirus and ureteric smooth muscle cell proliferation)

Specific viral pathogens
The spectrum of viral infections in the transplant recipient has enlarged with the discovery of new viruses (show table 5).The BK polyomavirus is been associated with infection of renal allografts with hemorrhagic cystitis, asymptomatic viruria, interstitial nephritis, ureteric obstruction, and rising creatinine values in renal transplant recipients [39-41] . (See "Clinical manifestations and diagnosis of JC; BK; and other polyomavirus infections" and see "Clinical manifestations and diagnosis of JC; BK; and other polyomavirus infections"). Adenovirus may cause a similar hemorrhagic nephritis/cystitis picture diagnosed by culture or antigen detection/immunofluorescence. (See "Epidemiology and clinical manifestations of adenovirus infection").

HHV-6, -7, and -8 have also been identified in transplant recipients [42] . (See "Virology; pathogenesis; and epidemiology of human herpesvirus 6 infection" and see "Human herpesvirus 7 infection" and see "Disease associations of human herpesvirus 8 infection"). HHV-6 has been implicated as a cofactor in CMV infection (and vice versa) or may cause leukopenia and fever as part of a viral syndrome. The role of HHV-7 remains to be clarified. EBV, VZV, and HSV are also often activated during this one to six month period. EBV may be associated with the development of B cell non-Hodgkin's lymphoma, particularly in seronegative recipients of seropositive organs.

However, some cases of T cell, NK cell, and non-EBV related PTLD have been described. (See "Lymphoproliferative disorders following solid organ transplantation"). Herpes zoster of the skin (shingles) may occur; occasionally, patients present with cholangitis due to VZV. Human papillomavirus (HPV) is associated with anogenital and squamous cell cancers. Parvovirus B19 may also present in this time period with anemia unresponsive to erythropoietin or with myocarditis. Respiratory viruses remain important community-acquired pathogens, particularly in the lung transplant recipient [43] . Infections with these latter viruses predisposes the patient to the development of bacterial infections and graft rejection.

EVALUATION AND MANAGEMENT
The pursuit of diagnostic testing and the management of infection in a transplant recipient must be guided by a number of principles:

These hosts generally have fewer clinical manifestations of infection and few or no findings by conventional radiography. Thus, more sensitive imaging techniques such as computed tomographic (CT) scans and magnetic resonance imaging (MRI) are essential for assessing the presence and nature of infectious and malignant processes. The "gold standard" for diagnosis is tissue histology. No radiologic finding is sufficiently diagnostic to obviate the need for tissue. Multiple simultaneous infections are also common. Thus, invasive procedures that provide tissue for culture and histology must be employed early as a routine component of the initial evaluation of transplant recipients with infectious syndrome.

Ptients failing to respond to appropriate therapy may also need invasive diagnostic procedures. Serologic tests, which indicate past exposure to certain pathogens, are useful in the pretransplant setting to assess risk for relapse of latent disease but are not generally useful after transplantation. Patients, especially those receiving immunosuppressive therapies, do not reliably develop antibodies quickly enough during an active infection to enable a serologic diagnosis. Thus, quantitative tests that directly detect the protein products or nucleic acids of the organisms such as sandwich ELISA, direct immunofluorescence, or molecular assays (hybrid capture, PCR) should be utilized.

Transplant recipients are particularly vulnerable to organisms resistant to antimicrobial agents either from the hospital environment or through induction of antibiotic resistance in their flora during therapy (eg, inducible beta-lactamases). Sites at risk for colonization with resistant organisms (eg, ascites, blood clots, drains, lungs) can be sampled so that information is available to guide empiric therapy at times of clinical deterioration. Antimicrobial agents are of little use in the presence of undrained fluid collections, blood, or devitalized tissues. Antibiotics, used in lieu of definitive drainage or debridement, merely delay clinical deterioration and promote the acquisition of resistant microorganisms. Early and aggressive surgical debridement of such collections is essential for successful care.

FUTURE DIRECTIONS

Many important hurdles remain to be overcome in the diagnosis and treatment of infections to enhance the safety and success of solid organ transplantation. The initiation of a diagnostic evaluation for infection frequently begins when clinical symptoms become manifest. That is often late in the course of the disease in these immunocompromised patients. Further, accurate microbiologic diagnoses are needed to avoid unnecessary toxicities associated with therapy. Thus, invasive diagnostic procedures are often required to make an accurate microbiologic diagnosis [44-46] .

More advanced, quantitative laboratory assays utilizing molecular techniques or antigen detection would be welcome. However, currently, such tests often do not offer timely results and/or are prohibitively costly for routine use. Rapid, quantitative, cost-effective assays that do not depend upon invasive procedures are needed for the routine monitoring of transplant patients for common infections. The availability of such tests would allow the clinician to individualize prophylactic antimicrobial regimens and minimize drug-associated toxicity.

The evolution of pathogens (bacteria, viruses, fungi) with acquired resistance to common antimicrobial agents and the incidence of drug toxicity and allergy have limited the available antimicrobial strategies for transplant recipients. New prophylactic regimens are needed to increase the number of available antiviral and antifungal agents for prophylaxis and therapy and to treat drug-intolerant patients.