key: cord-024795-xa7ke70d
authors: Kaviani, Aaron; Ince, Dilek; Axelrod, David A.
title: Management of Antimicrobial Agents in Abdominal Organ Transplant Patients in Intensive Care Unit
date: 2020-01-24
journal: Curr Transplant Rep
DOI: 10.1007/s40472-020-00268-0
sha: 
doc_id: 24795
cord_uid: xa7ke70d

PURPOSE OF REVIEW: Early diagnosis of infections and immediate initiation of appropriate antimicrobials are crucial in the management of patients before and after organ transplantation. We reviewed the most recent literature and guidelines in this field and organized the current recommendations for healthcare professionals caring for critically ill organ transplant recipients. RECENT FINDINGS: The incidence of multidrug-resistant organisms is increasing. Multidrug-resistant Gram-negative bacteria comprise about 14% of organisms. Vancomycin-resistant enterococci bloodstream infections are also on the rise, as 20.5% of nosocomial enterococci are now vancomycin-resistant, changing empiric antibiotic selection. Fluconazole-resistant Candida species comprise up to 46% of cases of candidemia in hospitalized patients. Consequently, new guidelines recommend primary use of echinocandins in patients with candidemia who have moderate-to-severe disease. Finally, the incidence of emergence of ganciclovir-resistant cytomegalovirus infection in patients is 5–12%, requiring early recognition and change to alternative regimens in the case of poor response to therapy. SUMMARY: Bloodstream infections are a major cause of mortality and morbidity in solid organ transplantation. Mortality as high as 24% and 50% have been reported with sepsis and septic shock respectively. As such, bloodstream infections should be diagnosed rapidly and intravenous antibiotics should be started immediately. Appropriate resuscitation should be initiated and the number and/or dose of immunosuppressive drugs should be reduced. Proper source control must also be achieved with radiologic drainage or surgical intervention as appropriate. Initial antibiotic treatment of these patients should cover both Gram-positive organisms, especially in the presence of intravascular catheters, and Gram-negative bacteria. Echinocandins like caspofungin should also be considered especially in critically ill patients, particularly if a patient has been on total parenteral nutrition or broad-spectrum antibiotics.

Organ transplantation is one of the major advances of modern medicine. The dream of replacing a nonfunctioning organ, like a kidney or a liver, with a functioning organ became a reality in 1954, when Dr. Joseph Murray transplanted a kidney from one identical twin to the other [1, 2]. Over the past few years, there has been a significant improvement in survival and reduction in rejection after solid organ transplantation (SOT) as a result of more effective immunosuppression therapy. However, infections and particularly bloodstream infections (BSIs) still remain as a common complication and a major cause of death after transplant [3] [4] [5] .

Transplant recipients have an increased risk of developing infections due to the lifelong treatment with immunosuppressive drugs [6] . Another risk factor for infection is the presence of unrecognized infection in the donor or the recipient. Rejection, which is often treated with intensified immunosuppression, also increases the incidence of infections, particularly viral and nosocomially acquired pathogens [3] . In addition, cytomegalovirus (CMV) infection may increase the risk of other infections, including bacterial and fungal infections [3, 7, 8] .

Bacterial infections are very common in patients with endorgan disease prior to and after SOT, and represent one of the most important causes of progression of liver failure, development of complications, and death in patients with end-stage liver disease (ESLD) [9] . Nosocomial bacterial infections are the most common cause of infection in this group of patients in the first month after transplantation [3, 5, 10] . Furthermore, liver, pancreas, and intestinal recipients are especially at risk for fatal fungal infections, primarily caused by Candida species which may occur together with bacterial infections. The risk of fungal infection is also higher in patients with kidney failure and history recent hospitalization. Candidemia is associated with diabetes, antibiotic use, total parenteral nutrition (TPN), surgical drains, and vascular access catheters. Delayed diagnosis because of low index of suspicion is common [11] [12] [13] [14] .

The complexity of treating SOT with life-threatening infections has been increasing dramatically given the increasing prevalence of multidrug-resistant organisms. Multidrugresistant Gram-negative bacteria comprise about 14% of organisms isolated in BSI after SOT. Recent studies show up to 20.5% of nosocomial enterococcal infections are vancomycinresistant. Fluconazole-resistant Candida species comprise up to 46% of cases of candidemia [12••, 15-17] .

Early diagnosis of infections and timely initiation of adequate antimicrobials are crucial in the management of patients before and after transplantation [9] . Patients also require assessment and adjustment of their immunosuppression and subsequent comprehensive evaluation for the source of infection. The goal of this review is to provide concrete actionable guidelines for clinicians caring for abdominal SOT patients with serious infections.

Infections are a major barrier prior to organ transplantation and all potential candidates should be evaluated for active infection [18] . Although we usually have the luxury of treating infectious diseases in most transplant candidates well before transplantation, progressive organ failure in patients with ELSD may mandate aggressive treatment of their infectious disease and urgent liver transplantation.

Patients with ESLD are prone to infections due to abnormalities of their immune system and bacterial translocation from bowel. Bacterial infections may be an eliciting factor for episodes of hepatic encephalopathy, gastrointestinal bleeding, kidney failure, hyponatremia, and development of acute-on-chronic liver failure [9] . Infections are usually caused by Gram-negative bacteria from intestinal origin, but Gram-positive bacteria are also common, particularly in hospitalized patients [9] . Fungal infections, mainly caused by Candida species, can also occur and are associated with high mortality rates [19] . Spontaneous fungal peritonitis (SFP) is associated with higher mortality compared with spontaneous bacterial peritonitis (SBP) [20] . Candida albicans is the most frequent fungal agent followed by Cryptococcus neoformans and Aspergillus species. Clinicians should also consider the presence of polymicrobial fungal infections. In fact, while polymicrobial bacterial infections affect 5.2-17.4% of cases, polymicrobial fungal infections occurred in 73.3-100% of patients with systemic fungal infections in a small case series [20] .

Due to high mortality and morbidity rate, SBP treatment should be initiated even in absence of a positive culture especially in patients with a higher Model for End-Stage Liver Disease (MELD) score. Patients with a positive fungal culture of the ascitic fluid regardless of polymorphonuclear leukocyte (PMN) count should also be treated. Antifungal drugs may also be started empirically for patients who are not responding to antibiotics [11] . Cefotaxime and ceftriaxone constitute the first-line treatment for community-acquired SBP and/or bacteremia, while broad-spectrum beta-lactams or carbapenems with or without vancomycin are considered the first-line treatment for nosocomial SBP and/or bacteremia [9] . Local resistance patterns should help guide empiric antibiotic therapy. Echinocandins like caspofungin should be considered empirical or preemptive therapy for patients with suspected SFP [20] . In patients with ESLD and SBP who are treated with antibiotics, intravenous administration of 20% albumin reduces the incidence of renal failure and decreased mortality rates from 29 to 10% [9] . Recommendations regarding empirical antibiotic treatment in patient with ESLD before liver transplantation have been summarized in Table 1 [9] . A personalized approach for first-line empiric antibiotic therapy needs to be chosen according to local epidemiology.

Infections after organ transplantation are commonly classified in 3 time periods: less than 1 month, first year, and after the first year.

The main sources of infection in the first month after SOT include donor-derived infections, preexisting recipient infections, surgical complications, and nosocomial infections including Clostridium difficile infection (CDI). Early removal of lines and drains, drainage of fluid collections, careful wound care, and judicious and limited use of antimicrobial agents help to reduce infections in this period of time [14, 24] .

The sources of infection in this period of time include surgical complications like anastomotic leaks, infected hematomas, cholangitis, and empyema as well as remaining nosocomial infections from previous month including CDI and residual pneumonia. Furthermore, opportunistic infections including viral infections, Pneumocystis jiroveci, Listeria monocytogenes, Toxoplasma gondii, Nocardia species, Aspergillus species, and endemic fungi usually happen in this period of time. Prophylactic measures are needed in this period of time to prevent opportunistic infections [14, 24] .

The risk of infection is less in this period of time in recipients with good graft function due to lower intensity of immunosuppressive agents. Sources of infection during this period include community-acquired viruses, foodborne gastroenteritis, molds from work or gardening, primary socially acquired CMV infection, relapsing viral infection, and infections related to underlying conditions like skin infections in diabetics. Patients with marginal allograft function who need higher levels of maintenance immunosuppression need more attention because of increased risk of recurrent infections including pneumonia, urinary tract infections (UTIs), cholangitis, and abscesses [14, 24] .

Infections are common after all types of SOT. However, some infections are more frequent in certain SOT recipients. In the following section, we address this issue in detail.

The most common infections in kidney transplant recipients include UTI (47%), viral infections (17%), pneumonia (8%), and wound infection (7%). UTIs are most commonly caused by Enterococcus species and Escherichia coli are the most common agents [25] . Kidney allograft pyelonephritis may be associated with bacteremia and sepsis and can be complicated by impaired graft function and even death [26] . BK virus can cause graft failure in kidney transplant recipients. However, with universal screening and treatment, reported graft loss due to BKV is only 0 to 5%. Careful immunosuppression adjustment is needed in these patients. Antiviral agents have a limited role. Intravenous immunoglobulin (IVIG) is occasionally used if there is persistent BK viremia after reduction of immunosuppression [27] .

The most common sites of infection in pancreas recipients include urinary tract and wound infections. Intestinal leaks in patients with enteric drainage happen in 5 to 8% of cases, resulting in abdominal abscesses requiring surgical or radiologic intervention. Most infections in pancreas transplant recipients are bacterial [28] . These patients are also at a higher risk for getting fungal infections and CMV given the greater intensity of immunosuppression and long-standing diabetes [12••, 28] .

In case of enteric drained graft leak, an abdominal computerized tomography (CT) scan with oral contrast should be done. Treatment comprises laparotomy and anastomotic revision which may include conversion of the enteric anastomosis from a side-to-side duodenojejunostomy to a Roux-Yduodenojejunostomy or a transplant pancreatectomy. For an early (≤ 2 weeks post-transplant) bladder-drained graft leak, low-pressure cystography or an abdominal CT with retrograde bladder contrast should be done. Foley catheter should be placed and percutaneous drainage of intraabdominal fluid collections should be performed. Peritonitis needs relaparotomy and direct leak repair or transplant pancreatectomy. Late leaks usually need conversion from bladder to enteric drainage [29] .

Major infections develop in 53-56% of liver transplant recipients [30, 31] . Bacterial infections are most frequent (70%), followed by viral (20%) and fungal infections (8%) [32•] . The most common bacterial infections include pneumonia, surgical site infection, abdominal cavity collections, abscesses, BSIs, and UTI [32•]. Many of these infections are associated with technical problems including bile duct stricture, biliary leaks, and hepatic artery thrombosis [15] . Laici and colleagues report pneumonia was the most frequent primary or associated infection and represented 40% of all infections after liver transplant. In 22% of cases, pneumonia led to the development of septic shock, which led to the death in more than 50% of affected recipients [32•] . Enterobacteriaceae are the major pathogens in LT recipients. Gram-positive bacteria are also a common cause infection [15] . LT recipients are also at a higher risk for getting fungal infections [12••] .

Bloodstream infections are the primary cause of mortality and morbidity in SOT. Mortality as high as 24% and 50% have been reported with sepsis and septic shock respectively. Nosocomial BSIs are associated with a higher rate of septic shock and mortality. Gram-positive bacteria are the most common cause of BSIs and tend to be associated with intravascular catheters. However, in kidney transplant recipients, Gramnegative bacteria are more common in BSIs, mostly associated with UTIs [12••, 16, 17, 33-37] .

Intravenous antibiotics should be started immediately. Appropriate resuscitation with goal-directed therapy including monitoring of markers of adequacy (lactate, central venous saturation, and end-organ perfusion) should be achieved. Furthermore, in severely ill patients, clinicians should rapidly reduce the intensity of immunosuppression. This includes stopping antiproliferative agents (e.g., mycophenolate mofetil) and mTORs (e.g., rapamycin) and lowering calcineurin inhibitor levels. Corticosteroids should be maintained to prevent adrenal insufficiency. The role of granulocyte colonystimulating factor (G-CSF) drugs is controversial, and G-CSF has been used by some centers for leukocyte counts of less than 3000 cells/mm [3, 38] . Proper source control, if possible, should also be rapidly achieved with radiological drainage or surgical intervention.

Initial antibiotic treatment of SOT patients with BSI should include coverage for probable source(s). Especially in the presence of intravascular catheters, Gram-positive pathogen coverage with vancomycin should be added to Gramnegative pathogen coverage [12••, 39-41] . Linezolid or daptomycin instead of vancomycin should be considered if there is a recent history of vancomycin-resistant Enterococcus (VRE) colonization or infection. Prior microbiologic history and local antibiotic resistance patterns in addition to possible source of infection should guide antibiotic therapy [12••] .

Echinocandins like caspofungin should also be considered in patients with septic shock without a focus especially in patients with risk factors for invasive candidiasis such as older age, central venous catheters, Candida colonization, total parenteral nutrition (TPN), prolonged neutropenia, prolonged intensive care unit stay, diabetes, renal replacement therapy, and/or broad-spectrum antibiotic therapy [42, 43] . Likewise, diagnosed candidemia requires treatment in all patients with either fluconazole or an echinocandin. One of the main differences between the newer vs. older guidelines is the primary use of echinocandins in patients with candidemia who have moderate-to-severe disease. However, empiric antifungal coverage is not needed if a patient does not meet above criteria [12••, 39, 44, 45] . Recommendations regarding initial antibiotic treatment of bloodstream infections and sepsis after SOT have been summarized in Table 2 [39, 42] . Initial management of different fungal infections after SOT has been summarized in Table 3 [39, 46, 47] .

Bacterial pneumonia is the most common cause of pulmonary infection in SOT candidates. Timing after transplantation, age, transplanted organ, degree of immunosuppression, site of acquisition of pneumonia, and exposures all play into the differential diagnosis in solid organ transplant patients [48••] . Community-acquired pneumonia and hospital-acquired pneumonia account for 40.7% and 59.3% of pneumonias in SOT, respectively. Hospital-or ventilator-associated pneumonia are typically diagnosed in the early post-transplant period with Pseudomonas aeruginosa, Gram-negative enteric bacteria, Acinetobacter species, Stenotrophomonas species, and Staphylococcus aureus, including MRSA as the most common pathogens in the peri-operative period. Opportunistic infections are most commonly seen in 1-6 months after transplant, and community-acquired pathogens, such as Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma species, Legionella species, and Chlamydia species, are more frequent after 6 months, though opportunistic infections can still be seen, especially if immunosuppression is increased for treatment of rejection.

Empiric treatment for pneumonia needs to be based on the above risk factors and timing after transplantation as well as the pace of illness onset. In nosocomial or ventilatorassociated pneumonia, nosocomial flora, and antibiogram and in lung transplant patients or in patients with prior pulmonary infections, organisms colonizing the airways and their susceptibilities should also be taken into consideration. For hospital-associated pneumonia and ventilator-associated pneumonia, The ID Society of America and American Society of Transplantation guidelines on pneumonia should be followed in conjunction with local antibiogram [48••, 49] . Broad-spectrum antibiotics with an activity against P. aeruginosa and other Gram-negative bacilli should be started empirically. For patients with septic shock and need for new ventilatory support, two agents with activity against P. aeruginosa can be considered. In patients with a high risk of mortality, prior intravenous antibiotic use within 90 days, hospitalization in a unit with > 20% MRSA prevalence, an anti-MRSA agent should also be started empirically. Empiric treatment should be modified based on previous microbiologic history and local antibiogram as well as patient's clinical response. An active agent against intracellular organisms and during the influenza season, anti-influenza agents are also recommended for empiric treatment until these infections are ruled out.

Respiratory viral infections, including CMV, are important causes of pneumonia among transplant recipients. Viral pneumonia predisposes the patient to superinfection with bacterial and fungal pneumonia. Treatment includes supportive care and reduction in immunosuppression (see CMV treatment below) [12••] . SOT recipients have a significant risk of invasive fungal infections (IFIs). Small bowel transplant recipients followed by heart-lung, liver, and pancreas transplant recipients have the highest rate of IFIs respectively [39, 46] . Although Candida species remain the most common cause of IFIs in SOT, molds comprise approximately 40% of IFIs in this group of patients. Aspergillus species cause the majority of mold infections. Mucormycosis is the next most common mold infection. Cryptococcosis and endemic fungi are other etiologies for IFIs [39, 47] . Echinocandins like caspofungin are recommended for treatment of Candida sp. However, the Infectious Diseases Society of America (IDSA) guidelines recommend voriconazole as the treatment of choice for invasive aspergillosis with isavuconazole and amphotericin B listed as alternative agents [50] . High-dose lipid formulation amphotericin B is recommended for mucormycosis, in combination with aggressive surgical debridement of infected tissues [39] . Recommendations regarding initial antibiotic treatment of respiratory infections after SOT have been summarized in Table 4 [39, 42] . Initial management of different fungal infections after SOT has been summarized in Table 3 [39, 46, 47] .

Central nervous system infections can be caused by donorderived infections, community-acquired organisms, and reactivation and/or acquisition of opportunistic pathogens. Cryptococcus, Nocardia, Aspergillus, Zygomycetes, Strongyloides, and Toxoplasma can affect both the lungs and the brain [12] . Clinical presentation depends on the organism, but may be subtle due to lack of a robust immune system. History; physical examination including detailed neurologic examination; laboratory evaluation including viral polymerase chain assays or multiplex panels; serum cryptococcal antigen; blood, urine, and sputum cultures; chest radiograph; magnetic resonance imaging of the brain with contrast; lumbar puncture; electroencephalography for seizures; and possibly neurosurgical intervention including biopsy and debridement are key elements in the evaluation of these patients [51] . Recommendations regarding initial antibiotic treatment of central nervous system infections after SOT have been summarized in Table 5 [42] . A recently published Cochrane review did not show sufficient evidence in favor or against primary and secondary preventions of seizures with anticonvulsive agents in viral encephalitis; however, some experts continue to recommend antiepileptic medications in all patients with seizures and encephalitis [52] .

UTIs are the most common infection after organ transplantation and account for 45 to 72% of all infections and 30% of all hospitalizations due to sepsis in kidney transplant recipients. Complicated UTI including pyelonephritis can result in significantly impaired transplanted kidney function and even death [12••, 26] . While Gram-negative bacilli are the most common cause of UTIs, Enterococcus sp. and S. aureus can also lead to UTIs in patients with indwelling urinary catheters [12••] . Broad-spectrum antibiotics such as piperacillin/ tazobactam or carbapenems might be warranted, with deescalation based on culture results [42, 53] . Patient's history of prior urinary tract infections and the organisms identified also need to be considered. In severe infections such as septic shock, immunosuppression should be reduced and upper tract imaging should be obtained. Cystoscopic, percutaneous, or surgical procedures to relieve obstruction or to drain abscesses might be needed [53] .

Candida is the most common cause of fungal UTI in kidney transplant recipients. Asymptomatic candiduria occurs in 11% of kidney transplant and does not require treatment. In these situations, urinary catheters should be removed or exchanged and second urine sample should be collected. Persistent candiduria in patients who does not have urinary catheter needs upper urinary tract imaging to evaluate for anatomic abnormalities and fungus balls. Asymptomatic candiduria should not be treated. Fluconazole is the treatment of choice for UTIs with susceptible Candida sp. Echinocandins are considered to be drugs of choice in unstable patients with systemic candidiasis; however, they do not reach acceptable levels for treatment of UTIs and relapses may occur . Recommendations regarding initial antibiotic treatment of urinary infections after SOT have been summarized in Table 6 [42] .

Bile leak, biloma, and biliary stricture can occur after liver transplantation especially after living donor liver transplants and can be complicated by peritonitis, abscess, and cholangitis. Hepatic artery thrombosis can lead to biliary complications as well as hepatic necrosis, abscesses, and sepsis. Cholangitis is a common complication after liver Broad-spectrum Gram-negative coverage with also anaerobic activity should be started in patients with sepsis. Specific regimen needs to be tailored to the local antibiogram and follow institutional empiric treatment guidelines, which take into consideration institutional rates of extended-spectrum beta-lactamase-or carbapenemase-producing organisms as well as multidrug-resistant P. aeruginosa. If a patient has peritonitis or intraabdominal abscess, Gram-positive coverage (vancomycin or daptomycin in patients with history of VRE) and antifungals should be added [42, 54] . If there are any concerns for biliary stricture(s) or bile leak based on initial imaging, endoscopic retrograde cholangiopancreatography (ERCP) should be performed and stent(s) placement might be needed. Percutaneous transhepatic cholangiogram (PTC) is reserved for ERCP failure or conditions that preclude it like Roux-en-Y hepaticojejunostomy or gastric outlet obstruction . Recommendations regarding initial antibiotic treatment of hepatobiliary infections after SOT have been summarized in Table 6 [42] .

Diarrhea occurs in 22 to 52% of SOT patients and can be due to infectious causes including bacterial, viral, or parasitic infections as well as medications including mycophenolate mofetil side effect. Stool culture, ova and parasite testing, and multiplex PCR testing for a wide variety of pathogens, if available, are among the initial tests recommended. Imaging studies and endoscopy (esophagogastroduodenoscopy and/or colonoscopy) may be warranted [12••] .

Clostridium difficile infection is the most common hospital-acquired infectious diarrhea, and fulminant colitis can happen in up to 13% of recipients with CDI [12••] . Oral CMV colitis can occur after SOT and can potentially cause end-organ disease. Treatment includes oral valganciclovir or intravenous ganciclovir [12••] . While the incidence of ganciclovirresistant cytomegalovirus in patients on prophylactic valganciclovir is as low as 0-3%, the incidence of emergence of ganciclovir-resistant cytomegalovirus infection in patients receiving ganciclovir treatment is about 5-12% [58] . For patients whose viral loads fail to decline while on therapy, ganciclovir resistance test is recommended. For most patients with confirmed ganciclovir resistance, foscarnet is suggested [59] . Cidofovir is the other option when there is a concern for resistance [12••] . Letermovir has also shown promising results in these patients, though it has not been approved yet for this indication [60, 61] . CMV immunoglobulin is associated with limited efficacy [12••] . Recommendations regarding initial antibiotic treatment of enterocolitis after SOT have been summarized in Table 6 [42] .

Surgical site infections (SSIs) are a common and major complication in SOT and are reported to occur in 5-40% of these patients [62] . Risk factors for SSI following various organ transplant surgeries and the most common pathogens have been summarized by Abbo et al. [63] . Infected wounds should be opened and washed out. Imaging for evaluation of possible deeper abscess should be performed and aspirates from these collections should be sent for cultures are recommended [42] . Source control is needed for treatment of deep SSIs and organ space infections. For SSIs, empiric treatment should include Gram-positive organisms as well as expected flora at site of transplanted organ, with broad-spectrum agents reserved for patients with risk for multidrug-resistant organisms [63] .

Recommendations regarding initial antibiotic treatment of wound infection after SOT have been summarized in Table 7 .

Transplant recipients have an increased risk of developing infections due to the lifelong treatment with immunosuppressive drugs. There should be a high index of suspicion in these patients and infections should be diagnosed rapidly. Early imaging is required. A multidisciplinary approach to the management of these patients which should include transplant surgery, infectious disease, and possibly interventional radiology as well as gastroenterology is needed. Appropriate resuscitation should be initiated and intravenous antibiotics should be started immediately. The number and/or dose of immunosuppressive drugs should be reduced. Proper source control must also be achieved with radiologic drainage or surgical intervention.

Conflict of Interest The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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