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Infections After Transplantation
Despite the remarkable surgical advances in orthotopic liver transplantation (OLT) and the development of many effective prophylactic strategies, infection can still be a frequent cause of morbidity and mortality after transplantation. The spectrum and manifestations of these infections are broad and variable and often reflect the fact that a patient awaiting liver transplantation is a unique host who is usually in an impaired state of health before transplantation, undergoes a technically complex operation, and then requires lifelong immunosuppressive therapy, which may be intensified as a result of rejection. For these reasons, if an infectious process is not identified early enough and treated appropriately, it can have devastating consequences. Conversely, recognition of infection can be problematic because symptoms of infection may mimic rejection and it may be difficult to distinguish between true infection and mere colonization.
Before the availability of current prophylactic regimens, 60% to 80% of all liver transplant patients experienced infection. The average number of infections per infected patient ranged between 1.5 and 2.5. Historically infections contributed to more than half of the reported cases of mortality after liver transplantation. In one series, infections were associated with 89% of all deaths, even after the availability of cyclosporine. In another report, the incidence of infection-related mortality was noted to be higher than 50% before 1980, 25% to 35% in the 1980s, and less than 10% in the 1990s. These reports are indicative of a high-risk subpopulation of patients who suffer multiple infectious episodes that are sometimes fatal. The incidence of infectious complications in OLT recipients is generally greater than that reported in other solid organ transplant (SOT) recipients. The Model for End-Stage Liver Disease (MELD) continues to be used to prioritize candidates for OLT. Patients with the highest MELD scores generally receive organs first. However, this practice has contributed to the increasing performance of transplantation in more critically ill patients who have a greater risk for infection. This chapter provides an overview of the time course, risk factors, clinical features, diagnosis, and management of infectious complications in OLT.
Pretransplant Screening: Recipient and Donor
Before OLT, several factors may predispose an OLT candidate to infection after surgery. Of these factors, identification of latent infections that may be reactivated in the presence of postoperative immunosuppression and recognition of active infection that may require therapy or preclude OLT are most significant. Latent infections or active infections in the pretransplant period can lead to reevaluation of transplant candidacy or alterations in standard posttransplant management. Untreated or unrecognized infections in the recipient can become clinically apparent in the posttransplant period. Recent data suggest that OLT recipients may be at higher risk for donor-derived bacteremias. Although donor-derived bacterial infections have been extremely rare in University of California at Los Angeles (UCLA) liver transplant patients despite frequently positive bacterial cultures in hospitalized liver donors, any infection, such as pneumonia or smoldering intra-abdominal, hepatobiliary, or genitourinary tract infection, can be reactivated or exacerbated in the immediate postoperative period during induction immunosuppressive therapy or later in the posttransplant period, depending on the overall net state of immunosuppression.
General Screening
Evaluation of patients for infectious disease before transplantation should include a meticulous history of antibiotic allergies, dental assessment, preoperative urine culture, and a chest radiograph to exclude active pneumonic processes and identify evidence of previous granulomatous disease. The risk for latent infection with tuberculosis (TB) or a geographically related endemic mycosis should be determined by eliciting a travel and residency history because old “healed” granulomatous lesions, such as TB, histoplasmosis, or coccidioidomycosis, can become reactivated in the posttransplant setting under conditions of routine immunosuppression or after treatment of rejection. The current screening method for TB infections relies on the tuberculin skin test (TST). However, the TST has two main limitations: a lack of specificity in patients who were previously vaccinated with the bacille Calmette-Guérin vaccine and diminished sensitivity in immunosuppressed patients. Furthermore, there may be variability in the performance and reading of the test and difficult compliance with the follow-up visit required to read the test. New in vitro T cell–based interferon-γ release assays (IGRAs; QuantiFERON-TB Gold), which use specific Mycobacterium tuberculosis antigens, have been developed in recent years. In comparison with the TST, IGRAs have higher specificity and equal or greater sensitivity for the detection of TB and latent infection in normal hosts. Because IGRAs have been associated with lower sensitivity in patients with immunosuppression-associated conditions versus immunocompetent people and because a deterioration of liver function can damage the cellular immune response, the performance of these tests may be compromised in patients with end-stage liver disease. Although several studies support the regular use of the QuantiFERON-TB Gold test for the screening of end-stage liver disease patients for latent TB infection before OLT, the use of IGRAs in TB screening and treatment decisions should be guided by the relative risk for possible toxicity of prophylactic antituberculosis drugs compared to the risk for active tuberculosis after transplantation.
The American Thoracic Society recommendations for isoniazid prophylaxis include most SOT recipients. However, the potential for isoniazid-induced hepatotoxicity and its confusion with graft rejection or dysfunction may prohibit routine prophylaxis in OLT recipients. At UCLA we do not recommend isoniazid for OLT candidates with positive TST or QuantiFERON-TB Gold test results unless conversion has been recently documented or significant abnormalities consistent with previous TB are present on chest radiography. Generally, patients who previously completed a full treatment course for active TB do not require additional antituberculous therapy after liver transplantation. However, early diagnosis and treatment are essential in organ transplant recipients.
Serological Testing
Preoperative serological testing should include the following: human immunodeficiency virus (HIV) antibody by enzyme immunoassay, with confirmation by Western blot analysis if warranted; hepatitis B virus (HBV) surface antibody, surface antigen, and core immunoglobulin (Ig) G and IgM antibody; hepatitis C virus (HCV) antibody or RNA detection assay as warranted; herpes simplex virus (HSV) antibodies; varicella-zoster virus (VZV) antibody; cytomegalovirus (CMV) antibody; Epstein-Barr virus (EBV) antibody; and specific endemic mycosis antibody tests when applicable (e.g., anticoccidioidal antibody detection in any patient with exposure to an endemic area).
Human Immunodeficiency Virus
All potential OLT recipients should be tested for HIV antibody regardless of risk factors. HIV-positive patients meeting specified criteria now undergo transplantation at some centers, but long-term outcomes of these patients have not been established. All potential transplant donors, both living and deceased, should be tested for HIV regardless of risk factors. Many centers reject livers from high-risk donors for fear of failure to detect antibody during the “window” after acute infection. Although transmission of HIV by infected organs has been described, these screening precautions have reduced the risk for infection to a negligible degree in the modern transplant era.
Epstein-Barr Virus
Both EBV-seronegative recipients of grafts from EBV-seropositive donors and EBV-seropositive recipients may be at increased risk for posttransplantation lymphoproliferative disorder (PTLD), particularly if they receive prolonged or repeated courses of antilymphocytic therapy or are pediatric allograft recipients. In high-risk patients the quantitative EBV viral load can be assayed by polymerase chain reaction (PCR) after increasing immunosuppression or when clinically indicated.
Hepatitis B and C
Historically, recurrent disease developed in most patients undergoing OLT for hepatitis B or hepatitis C. Current prophylaxis with hepatitis B immune globulin and antiviral agents has minimized recurrence of hepatitis B and improved patient and allograft survival rates similar to those of patients transplanted without hepatitis B. Recently a combination of oral antiviral agents (such as entecavir and tenofovir ) has replaced the use of hepatitis B immune globulin in selected OLT recipients at our center. In contrast, recurrence of hepatitis C is universal, and effective strategies are still needed to minimize disease recurrence and progression during the posttransplant period (see Chapter 11 ). Detection of HBV and HCV in both transplant donors and recipients has improved with newer laboratory methods designed to detect viral-specific antibody, antigens, and nucleic acids. In fact, hepatitis B core antibody–positive donors are used under stringent protocols with antiviral prophylaxis (i.e., lamivudine and hepatitis B immune globulin) in several liver transplant centers. Previously, HCV-positive donors were rarely used because of concern for transmission of a different or more virulent strain of HCV into an immunocompromised host and a lack of effective preventive therapies. However, recent studies have reported the outcomes of transplanting HCV-positive allografts into HCV-positive recipients. Several single-center reports have demonstrated that survival rates were not statistically different compared with those recipients receiving an HCV-negative allograft. In one report the HCV recurrence rate was lower in HCV-positive recipients with an HCV-positive allograft compared with those who received an HCV-negative allograft, suggesting a benefit of transplanting HCV-positive allografts. Ultimately, the conclusion from all these studies is that HCV-positive allografts free from fibrosis or severe inflammation are a safe option for HCV-positive recipients. These findings have also been observed in several analyses of the United Network for Organ Sharing (UNOS)/Organ Procurement and Transplantation Network (OPTN) database.
Cytomegalovirus
Before the availability of effective prophylaxis, CMV had been the most common viral pathogen after OLT. CMV infection may vary in severity from asymptomatic infection to multiorgan involvement. The incidence of CMV seropositivity increases with age such that most adult patients have detectable IgG antibody to CMV. Primary CMV infection is more severe than reactivated infection after transplantation. Thus seronegative patients should be considered candidates for prophylaxis at the time of OLT. The clinical significance of the CMV antibody status of the donor and recipient is discussed later in this chapter.
Cryptococcus, Coccidioidomycosis, and Histoplasmosis
Detection of Cryptococcus neoformans by the presence of antigen, Coccidioides immitis antibody by complement fixation or immunodiffusion, or Histoplasma capsulatum antibody by immunodiffusion during transplant evaluation should alert the clinician to the possibility of reactivation of disease after transplantation. Reactivation can occur during routine immunosuppression or after augmented immunosuppression for rejection. Patients who have resided in geographical areas endemic for coccidioidomycosis or histoplasmosis should be tested for antibody before transplantation. If antibody is present or if there is radiological evidence of residual disease, patients should receive appropriate prophylactic azole antifungal therapy.
Other Pathogens
Spontaneous bacterial peritonitis, cholangitis, respiratory tract infection, Clostridium difficile , and nosocomial fungal infection are frequently encountered infections in candidates for OLT. With the exception of invasive Candida or Aspergillus infection and overwhelming pneumonia, these infections do not preclude successful transplantation as long as adequate treatment is given and clinical improvement is documented before transplantation.
Donor- and Allograft- Transmitted Infections
It is sometimes difficult to differentiate between a donor allograft source of infection, exogenous infection, or reactivation of latent disease. The following agents have been implicated with reasonable certainty as being transmissible with the donor allograft: HIV, CMV, HBV, HCV, and H. capsulatum . Probable transmission has been reported with HSV; aerobic gram-positive and gram-negative bacteria; anaerobes; atypical mycobacteria; and EBV. Potential serious consequences of such transmission include infectious disruption of the vascular anastomoses, formation of mycotic aneurysms, infective endocarditis, and sepsis. The incidence of true donor-transmitted infection can be reduced by scrupulous screening and epidemiological evaluation, as discussed in Chapter 33 .
Time of Occurrence of Posttransplant Infections
Of all infections, 50% to 60% are bacterial, 20% to 40% are viral, and 5% to 15% are fungal. Less than 10% are due to parasites such as Toxoplasma . The type, severity, and incidence of observed infections often depend on prophylactic practices. Because there is some standardization of immunosuppressive regimens among liver transplant centers, a timetable for determining when postoperative infections are most likely to occur has been developed ( Fig. 78-1 ). Knowledge of this timetable may allow the clinician to form a differential diagnosis, initiate monitoring procedures for infection, and implement pharmacoeconomically effective management strategies.
Generally there are three time frames during which liver transplant recipients may develop infection: the first postoperative month, between 1 and 6 months after transplantation, and beyond the 6-month postoperative period. Notably, most infections occur in the first 2 months after liver transplantation, a time that corresponds to the period of most episodes of rejection and increased immunosuppression.
In the first month after transplantation, infections are associated with either pretransplant conditions or postoperative complications (see later). Most bacterial, as well as some fungal, infections are observed during this period. Of interest, the onset of fungal infection in OLT recipients occurs earlier than in other SOT recipients. Of these fungal infections, greater than 90% are Candida infections involving intra-abdominal organs, wounds, or intravascular catheters.
After this early period, reactivated or primary CMV infections may occur and peak around the sixth week after transplantation. HSV viral reactivation occurs earlier, whereas EBV infection may have a delayed onset. Infections with Pneumocystis jiroveci (previously known as Pneumocystis carinii ) and toxoplasmosis occur later during the first 6 months after transplantation and rarely beyond this period. ∗
∗ References .
Infections beyond the sixth month after transplantation are uncommon and occur primarily in patients with recurrent or chronic rejection, biliary or vascular complications involving the liver graft, or patients requiring repeat transplantation. Many late-onset infections also include infections commonly found in nontransplant patients, such as community-acquired viral or bacterial respiratory tract infections, urinary tract infections, or varicella-zoster infection. Events that affect the net state of immunosuppression, prolonged hospitalization, retransplantation, and new nosocomial or environmental exposures may alter the anticipated time course for infections in OLT recipients.
Risk Factors for Infections
The overall state of health of the patient and the urgency of the transplantation may affect the type and severity of postoperative infections. Specific risk factors for infection in OLT recipients include underlying medical conditions, environmental exposures in the community or hospital, technical complications of the transplant surgery, and the net state of immunosuppression (pharmacological and disease state related) ( Table 78-1 ). Knowledge of these risk factors may allow identification of OLT recipients at greatest risk for infection and the implementation of appropriate prophylactic and therapeutic strategies. Pretransplant, intraoperative, and posttransplant risk factors are reviewed in the following sections.
TABLE 78-1
Risk Factors for Infection In Liver Transplantation
| Pretransplantation | Transplantation | Posttransplantation |
|---|---|---|
| Underlying Medical Condition | Surgery | Postoperative Management |
| Corticosteroid therapy | Prolonged procedure | Indwelling vascular or bladder catheters |
| Poor nutritional status | Increased transfusion requirement | Prolonged intubation |
| Chronic lung disease | Graft ischemia or injury | Prolonged antibiotic administration |
| Diabetes mellitus | Intra-abdominal bleeding | Repeat laparotomy |
| Bowel leak | Repeat transplantation | |
| Choledochojejunostomy |
| Colonization | Donor Graft | Hospital Flora |
|---|---|---|
| Preoperative antibiotics | Cytomegalovirus | Resistant bacteria |
| Duration of hospitalization (especially in ICU) | Hepatitis viruses | Aspergillus |
| Human immunodeficiency virus | Legionella |
| Latent Infection in Recipient | Immunosuppression | |
|---|---|---|
| Cytomegalovirus | Cyclosporine | |
| Herpes simplex virus | Tacrolimus | |
| Varicella-zoster virus | Azathioprine | |
| Hepatitis viruses | Mycophenolate mofetil | |
| Endemic mycosis | Corticosteroids | |
| ( Coccidioides, Histoplasma ) | Alemtuzumab | |
| Pneumocystis | Thymoglobulin | |
| Tuberculosis | Sirolimus |
ICU , Intensive care unit.
Pretransplant Period
Previous medical conditions, chronic underlying diseases, renal failure (hemodialysis), fulminant hepatic failure, mechanical ventilation, malnutrition, a high MELD score, and diabetes mellitus are pretransplant factors that may predispose allograft recipients to infection (see Table 78-1 ).
Infections in the pretransplant setting are also associated with environmental factors. Potential bacterial environmental pathogens include Pseudomonas species and Legionella , which may contaminate water supplies, and Listeria and Salmonella , which have been associated with food-related epidemics. Significant community-related fungal exposure includes endemic mycoses ( C. immitis , Blastomyces dermatitidis , and H. capsulatum ), and C. neoformans . †
† References .
Exposure to nosocomial fungal pathogens such as Aspergillus and Candida is also concerning. ‡
‡ References .
With respect to Aspergillus infection, an association with hospital construction or water has been described. Furthermore, domiciliary and nondomiciliary patterns are possible. Domiciliary exposure occurs in the room or ward where the patient is housed, whereas nondomiciliary exposure occurs when the patient travels for a procedure and is exposed en route or at the destination site (radiological suite, operating room, catheterization, or laboratory). Additional risk factors for these pathogens include central venous or urinary tract catheters, extended use of systemic antibiotics or corticosteroids, colonization by a fungal pathogen, total parenteral nutrition, and contaminated air conditioning or filtering systems.
Intraoperative Period
Equally important are factors pertaining to the surgical procedure. For example, disruption of the integrity of the gastrointestinal tract by surgery or anastomotic leaks create an avenue for infections by endogenous flora. Any technical complication that leads to devitalized tissue, vascular thrombosis, or accumulation of fluid may also enhance the risk for infection. Additionally, vascular access devices and drainage catheters present a risk for infection in an OLT recipient because these devices disrupt the physical barrier to infection and produce portals of entry for endogenous and nosocomial organisms. The transplanted liver may also become a focus of infection as a result of vascular-related ischemia or rejection. Infections are also more common in OLT recipients who require a high number of intraoperative blood products, prolonged operative time, a choledochojejunostomy compared to a choledochocholedochostomy, retransplantation, or repeat laporatomy. Transfusion-associated infections caused by CMV or hepatitis viruses may also occur in OLT recipients receiving large amounts of blood products.
Posttransplant Period
Retransplantation, prolonged ventilatory support, renal failure, extended renal replacement therapy, prolonged use of antimicrobial agents, colonization with resistant hospital flora, and the net state of immunosuppression play a critical role in the development of infections in the posttransplant setting. The net state of immunosuppression has been reviewed by others and is considered to be a function of the dosage, duration, and temporal sequence of immunosuppressive therapy, any underlying immune deficiency, integrity of the mucocutaneous barriers, metabolic conditions, and infection with immunomodulating viruses. Additional diagnostic tools for predicting infection based on immune cell function have also been reviewed. ImmunKnow is a Food and Drug Administration (FDA)-approved in vitro assay designed to measure increases in intracellular adenosine triphosphate following CD4 cell activation. ImmuKnow provides an assessment of cellular immune function and has been used for assessing the risk for infection in adult liver transplant recipients. Furthermore, the assay may also identify OLT recipients at risk for rejection based on adenosine triphosphate immune response levels. Immunosuppressive agents continue to have the greatest impact on host susceptibility to infection. Various strategies are used to prevent rejection and depend on the type of transplant performed, the relative immunological risks for development of rejection, and the potential toxicity of immunosuppressive agents. Based on these factors, agents such as cyclosporine, tacrolimus, corticosteroids, azathioprine, and mycophenolic acids (MPAs) with or without T cell–depleting agents (e.g., thymoglobulin, alemtuzumab) have been used in various combinations to reduce the risk for rejection. Cyclosporine and tacrolimus reduce interleukin-2 (IL-2) production, which subsequently inhibits mixed lymphocytic reactions and preferentially impairs immune reactions against the allograft. The overall incidence of infectious complications with cyclosporine or tacrolimus appears to be similar.
Pulses of corticosteroids and various antilymphocytic globulins administered for the treatment of rejection increase the risk for infection. Corticosteroids affect all aspects of immunity, and high doses have been associated with fungal but not CMV infection in solid organ recipients. Azathioprine and MPAs have antilymphoproliferative activity, but they can also cause neutropenia, which may predispose to bacterial infectious complications. The use of MPAs has not been clearly established to increase the risk for infections after OLT. T cell–depleting agents such as the polyclonal agent thymoglobulin or alemtuzumab are some of the most potent immunosuppressive agents currently available. Historically, muromonab-CD3 has been associated with an increase in infectious complications, caused primarily by CMV, EBV, and HCV. §
§ References .
The impact of thymoglobulin or alemtuzumab on infection in OLT recipients remains to be fully elucidated, but the type of infections reported following the use of these agents have been similar to those observed with muromonab-CD3.
An IL-2 receptor monoclonal antibody preparation (e.g., basiliximab) can also be used for the prophylaxis of acute organ rejection in conjunction with tacrolimus (or cyclosporine), with or without MPAs and corticosteroids. Although initial trials with this agent in renal transplant patients failed to demonstrate an increased incidence of infection, it remains to be seen whether this observation will continue in liver allograft recipients, especially when these agents are used in combination with other immunosuppressive drugs.
Sirolimus is also selectively used in OLT recipients for the prevention of rejection. This agent differs from cyclosporine and tacrolimus in its mechanism of action. Whereas cyclosporine and tacrolimus act by blocking calcineurin and inhibiting T cell–dependent growth factors such as IL-2 at the level of gene transcription through a Ca 2+ -dependent signal, sirolimus appears to inhibit growth factor–dependent proliferation of hematopoietic cells at a later stage of the cell cycle through a Ca +2 -independent signal (referred to mechanistically as a mammalian target of rapamycin [mTOR] inhibitor ). In initial studies, sirolimus has demonstrated efficacy equal to that of cyclosporine in maintaining heart and renal allografts. Although the drug has not been approved by the FDA for use in OLT recipients, it is still used in these patients in specific clinical situations such as for calcineurin-sparing purposes or in OLT recipients with hepatocellular carcinoma. In a study of renal allograft recipients, the incidence and severity of infections were somewhat greater with sirolimus than cyclosporine, although the number of patients experiencing infections was similar between the two groups. The risk for P. jiroveci infection may be greater in OLT patients receiving sirolimus; thus long-term prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) is recommended when sirolimus is used. More experience is required with sirolimus (or the newest mTOR inhibitor, everolimus) alone or in combination with other available immunosuppressive agents to further evaluate any possible association with infections in OLT recipients. Finally, the use of pretransplant antimicrobial agents such as rifaximin (for hepatic encephalopathy) appears to have a protective effect against early posttransplant infections in more severely ill adult OLT recipients without selecting for multidrug-resistant bacteria. Rifaximin is a nonaminoglycoside semisynthetic, nonsystemic antibiotic derived from rifamycin and is a structural analogue of rifampin. The drug acts by binding to the β-subunit of bacterial DNA-dependent RNA polymerase, resulting in inhibition of bacterial RNA synthesis and has activity against aerobic and anaerobic gram-positive and gram-negative microorganisms that can cause infection following liver transplantation.
Bacterial Infections
As a result of the decline in herpesvirus infections and fungal infections due to effective prophylactic strategies, bacterial infections now account for an increasing proportion of all posttransplant infections. The incidence of posttransplant bacterial infections varies among different transplant centers because of several factors: (1) differences in definition and documentation of infection and duration of follow-up; (2) differences in the type and severity of underlying disease and the number of transplants; (3) differences in the type and duration of antimicrobial agents used for bowel decontamination, systemic prophylaxis, and treatment of infections; (4) surgical technique; (5) duration of intensive care unit stay; (6) immunosuppressive strategies; and (7) different infection control measures (i.e., isolation of patients with resistant organisms, hand washing, glove and gown requirements). Specific risk factors for bacterial infection in OLT recipients include transplant surgery longer than 12 hours, pretransplant bilirubin concentration greater than 12 mg/dL, increased duration of antibiotic therapy (>5 days) during the immediate postoperative period, increased number of red cell (>25 units) or fresh-frozen plasma (>30 units) transfusions, and multiple abdominal operations. щ
? References .
Although any bacterial organism can cause disease after liver transplantation, common bacterial pathogens include gram-positive organisms ( Staphylococcus aureus , coagulase-negative staphylococci, Enterococcus faecalis , and Enterococcus faecium ) and gram-negative organisms (Enterobacteriaceae and Pseudomonas aeruginosa ) ( Table 78-2 ). ¶
¶ References .
In a study of bacteremic OLT recipients, aerobic gram-negative bacilli constituted 49% of all pathogens found in blood cultures. More recent data have suggested that an epidemiological shift toward a higher incidence of gram-positive infections is occurring in OLT recipients. Of the episodes of early-onset bacteremia in one liver transplant center, 70.7% were caused by gram-positive pathogens. Coagulase-negative staphylococci accounted for 37.8% of all bacteremias, whereas methicillin-resistant S. aureus (MRSA) represented only 4.2% of these cases. Others have reported a higher incidence of MRSA in OLT recipients, up to 23%. Common sites of infection with MRSA include vascular catheters (39%), wounds (18%), the abdomen (18%), and the lungs (13%). Crude mortality rates of up to 21% have been seen in these patients, with the highest rates occurring in those with bacteremic MRSA pneumonia or abdominal infections. CMV seronegativity and primary CMV infection were significant risk factors associated with the development of MRSA infection. Some centers now recommend screening for MRSA in high-risk patients being assessed for OLT because the rates of MRSA colonization may exceed 80% and have been associated with risk for later infection. Unfortunately, elimination of S. aureus nasal carriage in OLT candidates with such agents as mupirocin has not been successful in preventing postoperative S. aureus infection. Furthermore, emergence of glycopeptide-intermediate S. aureus has also been reported in liver transplant recipients.
TABLE 78-2
Common Bacterial Pathogens in Liver Transplant Recipients
| Bacteremia | Pneumonia | Intra-abdominal | Wound | Urinary Tract |
|---|---|---|---|---|
| Enterobacteriaceae | Enterobacteriaceae | Enterobacteriaceae | Polymicrobial | Enterobacteriaceae |
| Pseudomonas aeruginosa | Pseudomonas aeruginosa | Polymicrobial | Staphylococcus aureus | Pseudomonas aeruginosa |
| Coagulase-negative Staphylococcus | Staphylococcus aureus | Enterococcus | Enterobacteriaceae | Enterococcus |
| Staphylococcus aureus | Anaerobes ( Bacteroides spp.) | Pseudomonas aeruginosa | ||
| Viridans streptococci | Streptococcus | |||
| Enterococcus |
Infection or colonization by vancomycin-resistant E. faecium (VRE) has been reported in liver transplant recipients and has been associated with increased morbidity and mortality. #
# References .
The most common site of VRE infection is the abdomen, followed by the bloodstream, wound, and intravascular catheters. OLT patients infected with VRE generally have received more preoperative antibiotics, are more likely to have received vancomycin preoperatively, and have been hospitalized in the intensive care unit. Additional characteristics of OLT recipients infected with VRE included repeat laparotomy after OLT, pulmonary or renal failure, coinfection with other microbial pathogens, and biliary complications. Invasive infection with VRE has been associated with poor outcomes in OLT recipients, with mortality ranging from 60% to 82%; polymicrobial sepsis was the most common cause of death in several reports. Pretransplant VRE colonization has been reported in as many as 55% of candidates for liver transplantation. These patients represent a substantial reservoir for continued nosocomial VRE transmission. Measures aimed at reducing VRE colonization in critically ill individuals with high MELD scores or new transplant recipients should be pursued, because the risk for morbidity and mortality is greater in these patients. Agents used for the treatment of VRE infections are linezolid, daptomycin, quinupristin-dalfopristin, and possibly tigecycline. Of note, outbreaks of linezolid-resistant VRE have been reported.
Infections caused by multidrug-resistant gram-negative pathogens, especially P. aeruginosa and Klebsiella-Enterobacter species, have been documented in OLT recipients. At some transplant centers gram-negative bacilli with transferable resistance to extended-spectrum cephalosporins have been reported with increased frequency among liver transplant recipients. Most of these strains, predominantly Klebsiella pneumoniae and Enterobacter species, are resistant to all β-lactam antimicrobials except carbapenems. Additionally, outbreaks of infections due to extended-spectrum β-lactamase–producing K. pneumoniae or Escherichia coli , as well as infections due to K. pneumonia carbapenemase-producing bacteria have been observed.
Anaerobic pathogens are less prevalent in OLT recipients. Similarly, Nocardia , Legionella , and Listeria are uncommon but potentially significant pathogens. In one series, Nocardia was reported in 7 of 191 patients (3.7%) over a period of 3.5 years with a 35% mortality rate. Specific risk factors for Nocardia infection include early rejection, enhanced immunosuppression, neutropenia, and uremia. Nocardia infections are most commonly manifested as acute or subacute pneumonia, but hematogenous spread to the brain, skin and subcutaneous tissue, bone, and eye has also been reported. Infection by Legionella species is reported in less than 5% of transplant patients but can develop within 3 to 12 weeks postoperatively with a mortality rate of 29%. Specific risk factors for Legionella infection include excessive corticosteroid use, prolonged postoperative intubation, and contaminated hospital water supply despite superheating and hyperchlorination. Signs and symptoms of Legionella pneumophila infection include a nonproductive cough, temperature-pulse dissociation, elevated hepatic enzyme levels, diarrhea, hyponatremia, myalgia, and confusion. Radiographic findings consist of alveolar or interstitial infiltrates, frank cavities, pleural effusions, and lobar consolidation. Infections caused by Listeria species are often associated with a reduction of T cell–mediated macrophage activation and have infrequently been reported in OLT recipients. Listeria monocytogenes infection is most commonly manifested as meningoencephalitis, brain abscess, or bacteremia. Patients with cirrhosis may also have spontaneous bacterial peritonitis. L. monocytogenes infection typically occurs 6 or more months after transplantation. This late onset may be related to the routine use of TMP-SMX for Pneumocystis prophylaxis, because TMP-SMX also provides excellent coverage against Listeria . A substantial proportion of sporadic cases of listeriosis are associated with the ingestion of processed meat; patients should be instructed to eat only properly cooked meat and pasteurized dairy products.
Many of the bacterial infections occurring after OLT are similar to those observed following major abdominal surgery and include intra-abdominal infection, pneumonia, wound infection, urinary tract infection, intravascular catheter infection, and primary bacteremia. ∗a
∗a References .
Intra-abdominal infections account for the majority of localized bacterial infections. These infections include peritonitis, hepatic and extrahepatic abscesses, and cholangitis. Complications associated with the biliary anastomosis, biliary obstruction, and the presence of a splinting T tube are unique factors that may predispose patients to intra-abdominal infection. These complications may introduce bacteria into bile, allow them to multiply, and then prevent clearance of colonizing bacteria from the biliary tree. Of interest, in the immediate postoperative period, patients who undergo choledochocholedochostomy do not routinely have bacteria present in their bile. The primarily complication observed in these patients appears to be obstruction at the anastomosis, whereas in patients who require a Roux-en-Y choledochojejunostomy, reflux of bacterial organisms may occur. The incidence of intra-abdominal infections is greater in OLT recipients who require Roux-en-Y choledochojejunostomy or undergo retransplantation than in patients who receive one transplant or undergo choledochocholedochostomy. Other intra-abdominal infections may result from the accumulation of infected intra-abdominal fluid, although many fluid collections in the surgical bed are sterile. Aspiration plus culture of fluid collections is frequently required in OLT recipients who exhibit persistent fever.
OLT recipients may be predisposed to nosocomial bacterial pneumonia as a result of encephalopathy, aspiration, and prolonged intubation. Common nosocomial pathogens causing pneumonia include aerobic gram-negative bacilli ( Klebsiella-Enterobacter spp. and P. aeruginosa ) and S. aureus . During the immediate posttransplant period, any patient with evidence of pneumonia requires immediate evaluation to identify potential pathogens and appropriate therapy because mortality rates from nosocomial pneumonia can be as high as 40%. OLT recipients are also at risk for community-acquired bacterial pneumonia, which usually occurs several months after transplantation. Streptococcus pneumoniae , Haemophilus influenzae , S. aureus , or respiratory viral pathogens often cause such infections. Chest radiography is used to confirm the presence of pneumonia, but interpretation of the findings may be complicated by the almost universal presence of right-sided pleural effusion and right lower lobe atelectasis after surgery. Infection of the pleural space or empyema is rare.
Bacterial infections of the central nervous system (CNS) in liver transplant recipients are very uncommon but have high mortality (44% to 77%). Aggressive workup (lumbar puncture, magnetic resonance imaging [MRI] or computed tomography [CT], diagnostic needle aspiration, or biopsy of brain mass) and appropriate treatment are needed in a patient with fever and abnormal neurological findings to minimize mortality. Both asymptomatic and symptomatic bacterial infection of the urinary tract may also occur, usually as a result of indwelling catheters.
Systemic bacterial infections or bacteremias have been observed in up to 27% of OLT recipients, with mortality rates ranging between 13% and 36%. †a
†a References .
Bacteremia may result from several portals of entry, including the abdomen, wounds, infected intravascular catheters, biliary obstruction or leakage, loculated abdominal fluid, hepatic artery thrombosis, and hepatic infarction. Common pathogens include Enterobacteriaceae, P. aeruginosa , coagulase-negative Staphylococcus , S. aureus , Enterococcus , or viridans streptococci. In approximately a third of patients with bacteremia, no apparent source can be identified. ‡a
‡a References .
Pulmonary sources of bacteremia in OLT recipients are less common and seen in only 10% to 16% of patients with bacteremia. They are often associated with aspiration or endotracheal intubation. §a
§a References .
Bacterial infections in OLT recipients may be difficult to diagnose because the usual signs and symptoms of infection may be masked or absent as a result of the patient’s net state of immunosuppression. Additionally, allograft rejection, preservation injury, and graft ischemia can have clinical manifestations similar to those of infection. Specific diagnostic techniques involve noninvasive measures (cultures of blood, urine, sputum, wounds, bile, and drains) and invasive measures (angiography and liver biopsy) to distinguish infectious complications from ischemia or rejection of the allograft. A presumptive diagnosis of an abdominal or liver abscess can be made by CT or ultrasonography and confirmed by radiographically guided fine-needle aspiration. Specimens that can be used to identify the specific cause of posttransplant pneumonia include sputum, tracheal aspirates (in patients maintained on a ventilator), or bronchoalveolar lavage fluid. Although cultures of sputum and tracheal aspirates can readily be obtained, the results are often difficult to interpret with regard to bacterial colonization versus actual infection. Several unique laboratory tests are available for the diagnosis of Legionella infection, including serum antibody determination, use of immunofluorescent antigen detection or a DNA probe on pulmonary secretions, and urine antigen detection.
Treatment of Bacterial Infection
Use of antibacterial therapy can be considered under the following categories: (1) surgical prophylaxis : antimicrobial agents used to prevent a commonly encountered infection in the immediate postoperative period; (2) empirical therapy : antimicrobial agents initiated without identification of the infecting pathogen; and (3) specific therapy : antimicrobial agents administered to treat a documented pathogen.
Surgical Prophylaxis
Generally, prophylactic antibiotics should be directed against skin pathogens (e.g., staphylococci, streptococci) and intra-abdominal pathogens (enteric gram-negative bacteria). Ampicillin-sulbactam, cefoxitin, cefotetan, or vancomycin plus an aminoglycoside (penicillin-allergic patient) can be used for prophylaxis and should be discontinued within 24 hours to reduce the risk for superinfection with resistant bacterial organisms. The use of third- or fourth-generation cephalosporins, extended-spectrum quinolones, or extended-spectrum β-lactam plus β-lactamase inhibitor combinations for prophylaxis is discouraged because of concerns related to cost and the emergence of resistant organisms that may compromise the effectiveness of these antibiotics for treatment of established infections.
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