According to the Centers for Disease Control and Prevention, approximately 16 million operative procedures were performed in acute care hospitals in the United States in 2010.1 In 2015, the Organ Procurement and Transplantation Network reported that 30 973 solid organ transplantation (SOT) procedures were performed in the US.2 Although there has been progress in infection control practices, surgical site infections (SSIs) remain one of the most common healthcare-associated infections and a substantial cause of morbidity, prolonged hospitalization, and death.3-5
Antibiotic prophylaxis (ppx) in the perioperative period is the standard of care for nearly all surgical procedures, including SOT. Although there have been intermittent reports that question its efficacy,6,7 evidence points to a benefit of perioperative antibiotic ppx in reducing postoperative SSIs in SOT recipients.8-10 However, specific antibiotic regimens and durations vary widely across transplant centers and SOT procedures, and the quality of the evidence supporting specific practices is varied.11
Currently, there are no formal recommendations on perioperative antibiotic ppx in SOT outside of the “Clinical practice guidelines for antimicrobial ppx in surgery” by the Infectious Diseases Society of America, American Society of Health-System Pharmacists, Surgical Infection Society, and Society for Healthcare Epidemiology of America (IDSA/ASHP/SIS/SHEA guidelines). These provide general prophylactic antibiotic recommendations for SOT but do not address the unique circumstances of the transplant population.12 Thus, the IDSA/ASHP/SIS/SHEA guidelines are not used in many transplant centers in the United States. Given the complexities of SOT and the unique risks for SSIs, guidance that is more customized to each SOT scenario is needed. To date, no formal guidelines for antimicrobial perioperative ppx have been published by any of the SOT societies as well. In the absence of formal guidelines, we believe there is value in sharing possible best practices based on the available data. Consequently, in this article, we describe the epidemiology and risk factors for SSIs and the available evidence for different perioperative antibiotic ppx regimens individualized by organ transplant type. We also address specific situations unique to each organ and provide a possible approach to perioperative antibiotic ppx. The potential approaches to perioperative ppx outlined at the conclusion of each section in this article represent the opinion of the authors and reflect the approaches used at their institutions; these possible approaches will not be graded because they are not formal guidelines, and in many cases, there is very limited data on which to base these recommendations. Of note, this review will be focused on perioperative antibiotic ppx only; long-term infection ppx posttransplantation is outside the scope of this article.
GOALS OF PERIOPERATIVE ANTIBIOTIC PPX
The primary goal of perioperative antibiotic ppx is to minimize SSIs postoperatively. SSIs are categorized by the CDC per the anatomical space involved: superficial incisional infections, deep incisional infections, or organ/organ space infections. The infection must occur within 30 days of surgery or within 1 year of surgery if a prosthetic implant is used.13 Perioperative antibiotics are thought to minimize SSIs by decreasing the bacterial load in the surgical wound and thereby optimizing the environment for healing.
Reducing SSIs requires a multifaceted approach; antimicrobials alone are insufficient to prevent this complication. Minimizing surgical operative time, and optimizing sterile technique, surgical practice, and perioperative management of patient comorbidities as well as glucose and temperature regulation are also imperative to limit SSIs.14-18
PERIOPERATIVE ANTIBIOTIC PPX FOR SOLID ORGAN TRANSPLANT RECIPIENTS
SSIs are a significant issue in SOT. Depending on the organ transplanted and the era of the report, SSIs have been reported to occur in 3% to 53% of patients transplanted, with the highest rates observed in small bowel/multivisceral transplants (where SSI rates can reach over 90% when prosthetic mesh is used), followed by liver, and pancreas transplant (PT) recipients (Table 1).6,46 SSIs are costly; they have been found to extend the average hospital stay by 7 days, increase readmission rates, and increase the cost of hospitalization by nearly 100%.62,63 SSIs have also been associated with increased graft failure as well as mortality in SOT recipients.19,24,36,53,64 It is thus crucial that SSIs be minimized.
SOT recipients appear to be at uniquely high risk for SSIs, with higher rates among SOT recipients than among non-SOT recipients who undergo comparable clean or clean-contaminated procedures.54 SOT recipients are also at high risk of developing infections with antibiotic-resistant organisms.65-67 Infections with multidrug-resistant organisms (MDROs) have been associated with increased morbidity and mortality, particularly in SOT recipients.66,68 For example, 1 study evaluating outcomes among liver and kidney transplant recipients found that among those infected with a carbapenem-resistant Acinetobacter baumannii, 67% died due to the infection.68 The increased risk for infection, including SSIs, with MDROs is likely related to the high degree of pretransplant exposure to antibiotics and hospitals, which are known risk factors for development of MDRO colonization and infection.67,69
Given the increased risk for SSIs and the increased risk for SSIs due to MDROs among SOT recipients, the perioperative antibiotic ppx given to SOT recipients must be optimized to prevent and minimize the risk of these infections. Unfortunately, there have been only 2 prospective randomized clinical trials assessing the impact of antibiotic ppx on SSIs in SOT recipients, and both included fewer than 125 patients.70,71 Further, only 1 compared different regimens, and neither evaluated the impact of the duration of ppx on recipient outcomes. To our knowledge, there are no randomized trials that have evaluated the duration of perioperative antibiotic ppx in SOT recipients. Due to the dearth of literature, the IDSA/ASHP/SIS/SHEA guidelines are limited in their recommendations, which in turn limit their utility. Below, we have reviewed the literature that is available for each organ type.
PERIOPERATIVE ANTIBIOTIC PPX BY SOLID ORGAN TRANSPLANT TYPE
Epidemiology of SSIs
Renal transplant (RT) recipients experience the lowest rate of SSIs among all SOT types, with rates estimated between 3% and 11% (Table 1).6,19-21 SSIs in RT can involve the superficial soft tissue as well as deep organ space including perinephric abscess and pyelonephritis. SSIs have a significant impact on RT recipient outcomes when they do occur, however, with reduced graft survival in patients who develop a SSI posttransplant.19,72
Risk factors for SSIs in RT recipients (Table 2) include host factors such as diabetes mellitus (DM), obesity, chronic glomerulonephritis, reoperation; surgical factors such as ureteral leak, hematoma, intraoperative blood transfusion; allograft factors including acute graft rejection, delayed graft function; and immunosuppression factors including use of antithymocyte globulin, azathioprine, mycophenolate mofetil (MMF), or sirolimus.19,22,72-74
The most common organisms causing SSIs among RT recipients (Table 1) are Gram-positive organisms, including Staphylococcus aureus, coagulase-negative Staphylococci (CoNS), and Enterococcus species. Less commonly, Gram-negative organisms and yeast can also cause SSIs.6,22,23,85 As with most SOT types, there have been reports of increasing MDROs causing SSIs in renal transplantation including methicillin-resistant S. aureus (MRSA) and drug-resistant Escherichia coli.6,22
Perioperative Antibiotic PPX
There have been 2 prospective randomized controlled trials evaluating antibiotic ppx in renal transplantation. The first trial found that there was a significantly lower rate of SSIs during the first 5 days posttransplant in the group that was given ppx with cefuroxime and piperacillin compared with the group that did not receive antibiotic ppx; this difference did not persist at 14 days posttransplant.70 The second trial compared the use of vancomycin plus ceftriaxone to cefazolin alone for perioperative ppx and found no difference in the rate of postoperative infections between groups.71 There have also been several retrospective studies among RT recipients that have reported a lower rate of SSIs when antibiotic ppx is used perioperatively.8,86-90 Studies have not shown any improvement when multiple agents are used (rather than a single agent).70,71,88 Further, studies have shown no difference in SSI rates between those who are given an anti-Staphylococcal penicillin (PCN) and those who are given a cephalosporin.89 Rates of SSIs were also not found to be notably different in a study using a third-generation cephalosporin (ceftriaxone) as compared with studies in which first-generation cephalosporins were used.71,91 In contrast to these studies, however, there was 1 recent study that found a significant reduction in SSIs when amikacin was used in perioperative ppx as compared to a cephalosporin73; this may have been related to the fact that the predominant organisms causing SSIs in this study were extended-spectrum β-lactamase (ESBL) producing Enterobacteriaceae, which were resistant to cephalosporins but susceptible to amikacin. These data suggest that in most cases, a single first-generation cephalosporin is adequate for perioperative ppx but the local epidemiology of MDROs should be considered.
Given these data, the recommendation in the IDSA/ASHP/SIS/SHEA guidelines is to use a single first-generation cephalosporin for RT recipients.12 We agree with this approach and would similarly limit the ppx to 24 hours or less (see Table 3 for dosing details and for alternatives for PCN-allergic patients). However, we would consider altering this approach if the recipient is being treated for an infection at the time of SOT to adequately cover the known pathogens during the perioperative and intraoperative period. Further research is needed to determine whether pretransplant colonization (such as pretransplant bacteriuria) in the donor and/or recipient should impact the perioperative antibiotic ppx selection (see section below on recipient/donor infection or colonization with MDROs for further details).
- IDSA/ASHP/SIS/SHEA guidelines recommend a first-generation cephalosporin for 24 hours or less for perioperative antibiotic ppx in renal transplantation.
Pancreas and Pancreas-Kidney Transplantation
Epidemiology of SSIs
SSIs are reported to occur in between 9% and 45% of PT or simultaneous pancreas-kidney (SPK) transplant recipients (Table 1).24-33 This higher rate may be explained by the clean-contaminated nature of these procedures and the presence of DM in all PT recipients, which is a known risk factor for infections posttransplant. The type of SSI varies by the pancreatic duct drainage technique: when enteric drainage is used, SSIs involving intra-abdominal spaces are more common; when bladder drainage is used, SSIs involving the genitourinary tract, for example, urinary tract infections, are more common.25,30 If bladder drainage is used, urinary tract infection rates within the first 3 months posttransplant have been reported as high as 48%.30,92 SSIs have a significant impact on PT and SPK transplant recipient outcomes, because SSIs that involve the deep organ space have been associated with longer hospital length of stay, increased graft loss, and increased patient mortality.24,31-34
Risk factors for SSIs after PT or SPK transplantation (Table 2) include host factors such as reoperation; surgical factors including prolonged operative time, prolonged ischemic time (>4 hours), enteric drainage (rather than bladder drainage), posttransplant fistula, hand-sewn anastomoses (rather than stapled anastomoses), blood transfusion; donor factors such as an organ donor older than 55 years; and allograft factors such as acute tubular necrosis in the allograft or graft rejection.24,34,75,76 Of note, use of peritoneal dialysis (rather than hemodialysis) pretransplantation has not been associated with an increased risk for intra-abdominal infections posttransplantation,77 and there was no difference found in the SSI rate between patients who were given tacrolimus versus cyclosporine.78
The most common organisms causing SSIs in pancreas transplantation depend on the location of the SSI (Table 1). In superficial SSIs, S. aureus, CoNS, and Gram-negative organisms, particularly E. coli and Klebsiella species are most common.24,34 In deep organ space SSIs, Enterococci, Streptococci, anaerobes, Gram-negative organisms, and Candida species are more common.24 Overall, Gram-positive organisms dominate (about 66% of SSIs), with Gram-negative organisms and yeast occurring less frequently (around 19% and 15% of SSIs, respectively).35 As with other SOT types, there are reports of increasing MDROs, including 1 study published in 2009 that found the majority of SSIs at their center were due to Klebsiella species, and 42% of the Klebsiella species produced an ESBL.34
Perioperative Antibiotic PPX
There has been 1 randomized controlled trial evaluating antibiotic ppx in PT. This trial included predominantly RT recipients but there were also 24 PT recipients included; this study found no difference between vancomycin plus gentamicin versus cefazolin plus gentamicin when evaluating postoperative infections.71 Outside of this trial, there are only retrospective studies evaluating surgical ppx in PT recipients. These retrospective studies have shown a reduction in the rate of SSIs with the use of ppx from 7%-50% to 7%-33%.24,28,92-95 In a single observational study, fluconazole was shown to reduce the risk for Candida SSIs from 10% to 6% in PT.10
Because the most common type of SSI is superficial and caused by Gram-positive skin flora, the recommendation by the IDSA/ASHP/SIS/SHEA guidelines is to use a first-generation cephalosporin.12 In our experience, however, based on the diverse array of possible etiologies of SSIs, broader coverage may be indicated; a possible alternative would be to use ampicillin-sulbactam plus fluconazole (Table 3). There is, however, only anecdotal experience supporting this. As with every organ transplant type, we would also consider revising this regimen based on recipient and donor infection as described below.
Most studies among PT and SPK transplant recipients use a duration between 48 and 72 hours for antibiotic ppx.24,28,92-95 Fluconazole use has ranged from 1 to 28 days in studies and clinical practice.10 There are no data to specifically support a prolonged duration of antibacterial or antifungal ppx, so we typically limit the antibacterial coverage to 48 hours or less and the antifungal coverage to 14 days or less. In most cases, fluconazole does not need to be extended beyond a single dose; more prolonged durations should be reserved for patients with specific risk factors for fungal infection, including enteric drainage and simultaneous/prior renal transplantation96 (see Table 3 for dosing details and for alternatives for PCN-allergic patients).
- IDSA/ASHP/SIS/SHEA guidelines recommend a first-generation cephalosporin for up to 24 hours for perioperative antibiotic ppx in pancreas transplantation.
- A possible alternative would be to use ampicillin-sulbactam for 48 hours or less and a single dose of fluconazole. Consider longer durations of fluconazole for patients with specific risk factors for fungal infection.
Epidemiology of SSIs
SSIs in orthotopic liver transplantation (OLT) can involve the superficial soft tissue as well as deep organ space including peritonitis. SSIs are relatively common in liver transplant recipients, occurring in 10% to 37% of patients (Table 1).36-44 SSIs post-OLT have been associated with increased graft loss and mortality at 1 year.36,42
Risk factors for SSIs in liver transplantation (Table 2) include: host factors such as prolonged intensive care unit (ICU) or hospital stay, antibiotic use in the prior 3 to 4 months, DM, hemochromatosis, high pretransplant model for end-stage liver disease score, ascites, obesity, prior hepatobiliary surgery, prior liver or renal transplantation; surgical factors such as prolonged duration of surgery (>8-12 hours), Roux en Y biliary anastomosis, bacterial contamination due to entry into the gastrointestinal tract, more than 4 units of red blood cells required in surgery, anastomotic leak; donor factors such as donor infection; allograft factors such as acute rejection after liver transplant; need for renal replacement therapy (RRT) posttransplant; and immunosuppression factors such as use of muromonab-CD3 within the first week after transplantation.36-44,79-81 There was no difference found in the rate of SSIs between those patients given tacrolimus and those given cyclosporine immunosuppression.38
The most common organisms causing SSIs in OLT recipients are Gram-negative organisms (predominantly Enterobacteriaceae, Acinetobacter species, and more rarely Pseudomonas); there are also high rates of infection with Enterococci, S. aureus, CoNS, and Candida species (Table 1).37,39,43-45 OLT recipients have particularly high rates of MDROs reported, predominantly with vancomycin-resistant Enterococci (VRE) and ESBL-producing Enterobacteriaceae23; 1 study reported 13% of Enterobacteriaceae isolates were ESBL-producing among OLT recipients.45 Use of pretransplant antibiotics (eg, for spontaneous bacterial peritonitis ppx) has been associated with lower overall rates of SSIs but an increased risk for intra-abdominal infection posttransplant with an MDRO.43,44
Perioperative Antibiotic PPX
Due to the high rate of SSIs in OLT recipients, perioperative ppx is routinely used, although there are no prospective randomized controlled studies evaluating antibiotic ppx in this population. Further, observational studies have come to differing conclusions regarding whether there is any benefit to broader antibiotics over a first-generation cephalosporin. One study published in 2008 found no difference in the rate of SSIs when comparing amoxicillin-clavulanate with a first-generation cephalosporin.79 A second study, however, showed that there was an increased risk for Enterococcal SSIs when cefotetan was used rather than ampicillin-sulbactam.81 A larger study published in 2008 found that use of cefazolin was associated with a significantly higher risk for SSI than the combination of a glycopeptide plus aztreonam, suggesting broader coverage may be beneficial.37 Taking these all together, the IDSA/ASHP/SIS/SHEA guidelines recommend a third-generation cephalosporin plus ampicillin or piperacillin-tazobactam alone.12 We would propose that using ampicillin-sulbactam is another alternative with sufficient coverage of the relevant organisms (Table 3). There are no studies comparing these different broad-spectrum regimens. Duration of ppx should be 48 hours or less because there is no evidence to suggest a benefit of prolonged ppx.97 Of note, some centers also use antifungal ppx perioperatively in liver transplant patients. Though clinical practice varies, antifungal ppx should be considered if the patient has risk factors for fungal infection (see Table 3 for dosing details and for alternatives for PCN-allergic patients).98 Risk factors for fungal infections include prolonged operative times, excessive blood transfusion, renal insufficiency requiring RRT, fungal colonization, and reoperation.98 Posttransplant antifungal ppx is crucial to consider but is outside the scope of this article. There is no evidence to guide whether the perioperative ppx should be altered based on recipient colonization, including colonization with MDROs.
Of note, there has been no conclusive benefit demonstrated from use of selective bowel decontamination before liver transplantation, and this intervention is not currently recommended.115-117 There have been several small studies that have found a benefit from pretransplant prebiotics and probiotics (with prebiotics referring to nondigestible fiber), although the small sample sizes and case reports describing secondary infection with the organisms contained in probiotics limit support for their use.118-120 As such, the IDSA/ASHP/SIS/SHEA guidelines do not make any recommendations about this practice, and we do not typically recommend the use of prebiotics or probiotics.
- The IDSA/ASHP/SIS/SHEA guidelines recommend a third-generation cephalosporin plus ampicillin or piperacillin-tazobactam alone for up to 24 hours for perioperative antibiotic ppx in liver transplantation.
- Another alternative would be ampicillin-sulbactam for 48 hours or less; antifungals may be considered based on individual patient risk.
Intestinal and Multivisceral Transplantation
Epidemiology of SSIs
SSIs in small bowel (SB)/multivisceral (MV) transplantation can include superficial or deep soft tissue infections as well as intra-abdominal collections. The rates of SSIs in SB/MV transplantation are extremely high; between 14% and 53% of patients develop SSI (Table 1).46-48 If prosthetic mesh is used to close the abdomen, SSI rates between 25.7% and 100% have been reported.47 Infection during the first month posttransplant, particularly intra-abdominal infection, is associated with increased mortality in these patients.64
Risk factors for SSIs after SB/MV transplantation (Table 2) include: recipient factors such as increased age, hospitalization before transplantation, retransplantation; surgical factors including use of surgical mesh, reoperation in the first month, contamination of the surgical field, enterocutaneous fistulas, skin flaps, staged procedures; need for posttransplant RRT; and immunosuppressive choice, especially the use of daclizumab and MMF.48,64
SSIs after SB/MV transplantation are often polymicrobial and predominantly involve Gram-negative organisms, including Pseudomonas species and Enterobacteriaceae.49,50 Less frequently, Gram-positive organisms are found, including Enterococci and Staphylococci.48-50 Fungal infections including Candida species, as well as anaerobic organisms, are also commonly reported (Table 1).51,52 Extremely high rates of MDROs among SB/MV recipients are reported with one study noting that 31% of Enterobacteriaceae isolates were ESBL-producing, 36% of Pseudomonas isolates were multidrug-resistant, 75% of Enterococci were VRE, and 100% of S. aureus were MRSA among SB/MV recipients.49
Perioperative Antibiotic PPX
Although there are limited data concerning perioperative antibiotic ppx for SB/MV transplantation, it is routinely utilized due to the high rates of SSIs. In 1 study in which 43% of patients were given a standard regimen of ampicillin-sulbactam plus fluconazole, and the remainder were given a customized antibiotic regimen by Infectious Disease consultants, they found no difference in SSIs between the 2 groups.49 Notably, many patients were given ppx with an agent that covered the organism that was ultimately causative in the SSI, suggesting that antibiotic ppx alone is not sufficient to fully prevent SSIs in these patients.49 The IDSA/ASHP/SIS/SHEA guidelines do not provide recommendations for SB/MV transplantation. Due to the high rate of SSIs and the broad array of causative organisms, we would suggest a possible approach using a combination of antibiotics targeting Gram-positive (including Enterococcus), Gram-negative (including Pseudomonas), anaerobic, and fungal organisms (Table 3). Options include vancomycin plus cefepime, metronidazole, and fluconazole; or vancomycin plus piperacillin-tazobactam and fluconazole. There is no consensus on duration, though there is no evidence to suggest prolonging the duration beyond 72 hours is beneficial in uncomplicated cases. In patients with infected mesh or fistulas, prolonging the duration to 7 days may be needed.
- The IDSA/ASHP/SIS/SHEA guidelines do not provide recommendations for perioperative ppx for SB/MV transplantation.
- A possible approach would include vancomycin, cefepime, metronidazole, and fluconazole or vancomycin, piperacillin-tazobactam, and fluconazole for 72 hours or longer as needed in selected cases.
Epidemiology of SSIs
SSIs in orthotopic heart transplant (OHT) recipients can range from superficial soft tissue infections to sternal infections and mediastinitis. SSIs occur in between 4% and 19% of OHT recipients, and mediastinitis has been reported in 1.7% to 7% (Table 1).53-59 Development of a posttransplant SSI or nosocomial infection among OHT recipients is associated with increased risk for mortality.53
Risk factors for SSIs in heart transplant patients (Table 2) include host factors such as increased age, obesity, DM, prior cardiac procedure, prior ventricular assist device (VAD), prolonged mechanical ventilation, positive wire cultures or other sites of recipient colonization (especially with Gram-negative organisms), and reoperation or retransplantation; surgical factors such as prolonged ischemic time, use of bilateral internal mammary arteries; donor factors such as donor colonization (particularly with Gram-negative organisms); immunosuppression including early use of mechanistic target of rapamycin inhibitors; and ciprofloxacin monotherapy for ppx.53-55,58,82,83
The most common organisms causing SSIs in OHT recipients are CoNS, S. aureus including MRSA, Enterococcus, Enterobacteriaceae including ESBL-producing organisms, Pseudomonas aeruginosa, Stenotrophomonas, and Candida species (Table 1).55,58,59
Perioperative Antibiotic PPX
There is little data in OHT recipients regarding perioperative antibiotic ppx. However, there have been studies performed in patients undergoing other cardiac procedures, from which data may be extrapolated. In those studies, prophylactic antibiotics resulted in a significant reduction in postoperative SSIs.99-102 Regarding antibiotic choice, there is significant controversy. Studies have found no difference in SSI rates between anti-Staphylococcal PCNs (eg, methicillin) and cephalothin.99 However, when evaluating vancomycin versus cephalosporins, some studies show no difference,103-105 whereas others show a benefit of vancomycin over cephalosporins.106,107 The impact of vancomycin on SSI rates may be related to the prevalence of MRSA colonization and infection at each institution. The IDSA/ASHP/SIS/SHEA guidelines recommend using a first-generation cephalosporin alone for up to 24 hours in heart transplantation. However, because of the controversy regarding the superiority of vancomycin over cephalosporins, another option would be the use of vancomycin and a first-generation cephalosporin (Table 3). The optimal duration of ppx is unclear. In non-OHT cardiac surgery, it has been shown that 56 hours of ppx is not superior to 36 hours108; and in several studies, it has been shown that prolonging antibiotics beyond 48 hours does not reduce SSIs but does increase the rate of antimicrobial resistance.102,109 Our approach would thus extend antibiotics for a maximum of 48 hours postoperatively.
- The IDSA/ASHP/SIS/SHEA guidelines recommend using a first-generation cephalosporin alone for up to 24 hours for perioperative antibiotic ppx in heart transplantation.
- Alternatively, in patients colonized with MRSA or at transplant centers with a high incidence of MRSA, vancomycin plus a first-generation cephalosporin for up to 48 hours might be appropriate.
There are several unique situations in OHT that require customization.
- VAD: If there is a history of VAD infection, then coverage of that organism should be considered in the perioperative antibiotic regimen. Given the increased risk for Gram-negative infection associated with prior VAD use, even if there is no history of VAD infection, a possible approach would be to broaden the Gram-negative coverage to a third-generation cephalosporin or cefepime.110,111
- Extracorporeal membrane oxygenation [ECMO]: If the patient required ECMO as a bridge to OHT, there is no evidence to suggest that the antibiotic regimen should be altered, unless there is an active infection or colonization of the circuit, in which case the infecting/colonizing organisms may be covered in the perioperative antibiotic regimen.121
- Open chest: Delayed chest closure posttransplant is a significant risk factor for infection.122-124 Although there are no data to support broadening coverage in this scenario, one might consider including Gram-positive (including MRSA), Gram-negative (including Pseudomonas), and candidal coverage until the chest is closed, due to the higher risk for infection.
Epidemiology of SSIs
SSIs in lung transplant (LT) recipients can present in a variety of fashions, including superficial soft tissue infection, pneumonia, empyema, mediastinitis, and airway anastomotic infection. SSIs are relatively common post-LT and have been reported in between 5% and 19% of patients (Table 1).53,56,60 If all pneumonias in the early postoperative period are included, then the SSI rate is as high as 40%.53 Development of a posttransplant SSI is associated with increased mortality (approximately 35% mortality at 1 year posttransplant).53,60
Risk factors for SSIs after LT (Table 2) include host factors such as pretransplant colonization, DM, impaired renal function, prior sternotomy, repeat transplantation; surgical factors including prolonged ischemic time, blood transfusions, reexploration due to bleeding; and donor factors such as colonization of the donor bronchus and/or perfusate (particularly with a Gram-negative organism).53,60,61 A study of 115 LT recipients showed that LT recipients had significantly worse outcomes including longer ICU time, longer time on mechanical ventilation, and worse survival when the donor bronchoalveolar lavage culture grew bacteria.53,84
In contrast to other transplant types, the most common organisms causing SSIs in lung transplant recipients are Gram-negative organisms, particularly Pseudomonas species, E. coli, and Klebsiella species.60,61 Fungal organisms, including Candida and Aspergillus species, are also more common among lung transplant recipients than other SOT recipient types.60,61,121 Gram-positive organisms, including S. aureus, Enterococcus species, and CoNS, are still important but slightly less common.60,61 More rarely, Stenotrophomonas may also cause SSIs60,61 (Table 1).
Perioperative Antibiotic PPX
There are few studies evaluating perioperative antibiotics for lung transplantation and no randomized controlled trials. Retrospective studies have shown a reduction in posttransplant pneumonia with ppx but there is little guidance in the literature regarding either specific regimens or durations.112,113 Because of this, the IDSA/ASHP/SIS/SHEA guidelines recommend a single first-generation cephalosporin for ppx.12 Due to the frequency of Gram-negative and fungal SSIs in lung transplant recipients, however, many centers in the US utilize broader coverage. One potential approach would be to use vancomycin plus a third-generation cephalosporin or cefepime (Table 3). Antifungals may also be indicated; if there is a history of fungal colonization or infection in the donor or recipient, then the risk of fungal infection is increased and the use of an antimold azole may be considered.114 Some centers use universal antimold ppx though there are no studies to confirm whether this practice is warranted.121 If neither donor nor recipient had pretransplant infection or colonization with bacterial or fungus, then the antibacterial ppx may be limited to 48-72 hours.
- The IDSA/ASHP/SIS/SHEA guidelines recommend a single first-generation cephalosporin for perioperative antibiotic ppx in lung transplantation.
- An alternative approach would be vancomycin (particularly in centers with a high rate of MRSA) plus a third-generation cephalosporin or cefepime for 48-72 hours.
There are several unique situations that require customization.
- ECMO: If the patient required ECMO as a bridge to lung transplantation, there is no evidence to suggest that the antibiotic regimen needs to be altered, unless there is an active infection or colonization of the circuit, in which case the infecting/colonizing organisms may be covered in the perioperative antibiotic regimen.
- Pretransplant colonization: If the donor or recipient has a history of pretransplant pulmonary colonization/infection, as is often the case particularly in patients with cystic fibrosis (CF), those organisms that colonize the donor or recipient may need to be covered by the ppx regimen. There are no data to suggest an optimal duration of coverage, although most centers use at least 7 days of treatment. This is based primarily on reports of comparable outcomes among CF patients and non-CF patients when the CF patients were treated for 7 days based on their pretransplant cultures.125
- Open chest: Delayed chest closure posttransplant is a significant risk factor for infection.122-124 Although there is no data to support broadening coverage in this scenario, the authors’ routine practice includes covering Gram-positive (including MRSA), Gram-negative (including Pseudomonas), and fungal organisms until the chest is closed, due to the higher risk for infection.
CUSTOMIZATION OF ANTIBIOTICS BASED ON RECIPIENT AND DONOR COLONIZATION/INFECTION
Recipient Colonization or Infection
When the SOT recipient is colonized, or being treated for an active infection at the time of transplantation, the surgical ppx regimen may need to be reevaluated. This is largely because colonization may confer an increased risk for SSIs. For example, in lung and heart transplantation, it has been shown that recipient colonization with a Gram-negative organism increases the risk for posttransplant SSI and pneumonia.53 Another study evaluating rectal screening for MRSA and VRE in liver transplant recipients found that colonization with either organism was a risk factor for infection.126 In RT recipients, pretransplant colonization with a carbapenem-resistant Klebsiella pneumoniae (CRKP) isolate is associated with posttransplant CRKP bacteriuria, although it is not clear if this is associated with CRKP infection.127
Though pretransplant recipient colonization may increase the risk for posttransplant infection, there are no studies evaluating whether perioperative antibiotics targeted at recipient colonizers reduce the incidence of infection posttransplant. However, because colonization may increase the risk of infection, and because there is high attendant morbidity and mortality with SSIs in SOT patients, 1 approach would be to cover the known recipient colonizers in the perioperative antibiotic regimen. In lung transplant recipients, one might also consider extending the ppx to 7 to 14 days, based on literature from CF patients.125 This can be difficult when patients are colonized with MDROs, such as carbapenemase-producing Enterobacteriaceae. In those cases, pretransplant consultation with transplant infectious disease specialists is recommended to select the most appropriate regimen and duration on an individual basis. If the recipient is being treated for a prior active infection, that treatment should continue in the operating room and postoperatively as originally planned.
Donor Colonization or Infection
The impact of donor infection/colonization on recipient outcomes remains controversial. There are clear cases of donor-derived infections (DDIs) in the literature where donor bacterial infections were transmitted to the recipient. Further, there have been increasing reports recently of MDROs being transmitted from donors with bacteremia to recipients, including MRSA and MDR-Gram-negative organisms.128-135 Whether donor colonization is a source of recipient infection is less clear, although there have been studies suggesting donor colonization, at least of the transplanted organ, may be important. For example, 1 study performed in lung transplant recipients found that having positive donor bronchoalveolar lavage cultures (regardless of whether it represented true infection or colonization) was associated with longer ICU stays and decreased survival among recipients.84 This question is not yet settled, however, because other studies have not found any change in outcomes when the donor was colonized at the time of transplantation.136
It is also unclear if treating the recipient for positive donor cultures is consistently beneficial, because the impact of donor infection/colonization remains elusive. In case reports from the 1970s and 1980s, there were devastating outcomes associated with S. aureus and Pseudomonas DDIs including arterial anastomosis dehiscence.137,138 More recent studies have been inconclusive, although in many of those studies, the recipients received antibiotics to which the donor organism was susceptible, perhaps suggesting that the prophylactic antibiotics mitigated the risk of DDI.139 In a case series recently published by Mularoni et al,140 describing the outcomes of 30 recipients who had donors that were colonized or infected with an MDR Gram-negative at the time of transplantation, they found that among high-risk donations (where the MDRO was in the bloodstream or in the organ being transplanted), there were no transmission events when the recipient was given appropriate prophylactic antibiotics. In 4 cases where the recipient was not given appropriate antibiotics, there were transmissions of the MDRO to the recipient. This case series suggests that antibiotics targeted toward positive donor cultures may reduce DDIs. It further suggests that some types of positive donor cultures may pose a greater risk to the recipient than others, such as positive blood cultures or positive cultures from the allograft to be transplanted. Based on this, it is worth considering the use of perioperative antibiotic regimens that are active against the organisms that grow from donor cultures. Although there is no guidance from the literature on the optimal duration of antibiotics for positive donor cultures, 7 to 14 days of antibiotics is commonly used depending on the organism and the source of infection.141
ADMINISTRATION OF PERIOPERATIVE ANTIBIOTIC PPX
Though the choice of antibiotic regimen is of great significance, accurate timing of antibiotic dosing is equally important. Perioperative antibiotics have the most impact on reducing SSIs when administered within 60 minutes of surgical incision.142 If the antibiotic must be administered over 1 to 2 hours (eg, vancomycin or levofloxacin), the infusion should be started 120 minutes before the incision.12 All perioperative antibiotics should be given intravenously rather than enterally, as the time to therapeutic blood levels is faster and more predictable with the intravenous route. The perioperative dose should be weight-based, particularly in obese patients (including cefazolin, which should be increased to 3 g when the patient’s weight is over 120 kg12). During the procedure, redosing of antibiotics may be necessary, especially in the setting of cardiopulmonary bypass, depending on the half-life of the agent(s) being used. It has been shown that SSIs are less common when the perioperative antibiotics still have detectable levels after the procedure.142-145
The current recommendation is that antibiotics should be redosed intraoperatively if the procedure lasts more than 2 half-lives of the drug or if there is excessive blood loss during the procedure.12,142-145
THE CONSEQUENCES OF BROADENING PERIOPERATIVE PPX
With the high risk of SSIs in SOT recipients, and a rising incidence of MDROs in SOT donors and recipients, it seems logical to progressively broaden and extend perioperative antibiotic ppx. As such, it is worth noting the consequences related to overuse of perioperative antibiotic ppx and emphasizing how imperative it is to limit antibiotic exposure whenever possible. Although perioperative antibiotic ppx is only given for 24 to 48 hours in most cases, this antibiotic exposure may have significant downstream effects on quality of care and patient safety, including (1) increased rates of Clostridium difficile colonization and colitis,146-148 (2) increased rates of antimicrobial resistance,149 (3) increased adverse drug events, and (4) increased financial costs. Thus, targeted antibiotics should be used in each case based on individual risk factors and local patterns of resistance. Given the many gaps in data driving perioperative ppx in organ transplantation, future prospective studies are warranted to determine optimal regimens for transplant recipients. At this time, a consensus meeting among a diverse panel of specialists would be beneficial to determine best practice for perioperative ppx in SOT.
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