Numerous cases of unexpected tuberculosis transmission from donors to recipients have been reported in the literature (see Table 29). Given the difficulties of detecting tuberculosis in deceased donors, many of these cases involved donors with normal chest x-rays, no microscopic evidence of acid-fast bacilli, and/or negative cultures for M. tuberculosis. For example, in a case of multidrug-resistant tuberculosis in a lung transplant recipient in Hong Kong, the donor:a 51-year-old recent immigrant from China:had no history of tuberculosis, and chest x-ray, microscopy of tracheal aspirate, and cultures showed no evidence of M. tuberculosis infection. Other similar cases of donor-derived tuberculosis in solid organ recipients, in which the donor was negative for tuberculosis based on acid-fast bacilli stain, culture, and chest x-ray, demonstrate the importance of donor history in the assessment of potential tuberculosis risk.
Table 29 summarizes the tuberculosis risk factors present in donors who subsequently transmitted M. tuberculosis to 1 or more organ recipients. The most common risk factors among reported cases were recent arrival from or previous residence in an endemic country, followed by donor characteristics such as homelessness, alcoholism, incarceration, and health and hygiene status. Cases of drug-resistant tuberculosis transmission further emphasize the importance of donor history: in a recent Australian case of donor-derived tuberculosis in a lung transplant recipient, further investigation into the donor revealed a history of latent tuberculosis 5 years before death, which had been treated with 9 months of preventive isoniazid therapy despite the index case demonstrating M. tuberculosis resistance to isoniazid.
A retrospective Spanish study of deceased donors used between January 1998 and June 2011 found that, of 11 deceased organ donors with active M. tuberculosis infection at the time of transplantation, tuberculosis was transmitted to the recipients in 2 cases (transmission rate of 18.2%). The risk of tuberculosis is greater for lung transplant recipients than for recipients of other organs. Of cases of unexpected donor-derived M. tuberculosis transmission identified from the published literature, 15 (52%) of 29 were in single or bilateral lung transplant recipients. Moreover, in several cases of donor-derived M. tuberculosis transmission to lung recipients, it was reported that none of the same-donor organ recipients developed evidence of tuberculosis after several months of observation. Based on a literature review of donor-derived tuberculosis in lung transplant recipients reported by Mortensen et al in 2014, the median time to tuberculosis diagnosis was 88.5 days (range, 21-153 days). The most common presenting symptoms among reported cases were fever and dyspnea; however, in a large proportion of cases (>30%) M. tuberculosis was detected by protocol acid-fast bacilli smear or culture of respiratory specimens before the onset of symptoms (in these cases the median time to diagnosis was 68.5 days). Of the identified cases of donor-derived tuberculosis in lung transplant recipients, 3 (20%) of 15 were fatal. Another lung recipient died from causes unrelated to tuberculosis.
In recipients of nonlung organs, M. tuberculosis infection is more likely to present as extrapulmonary disease that is frequently difficult to diagnose. The most common presenting symptom is fever, though some patients may also experience nausea, cough, headache or a deterioration of renal function (see Table 29). Of the reported cases of donor-derived tuberculosis in kidney transplant recipients, 3 (27%) of 11 were fatal, with 1 additional death from unrelated causes.
Table 30 summarizes the 2012 recommendations of the Donor-Derived Infections Consensus Conference on M. tuberculosis with regard to clinical management of solid organ transplant recipients under different deceased donor scenarios. In summary, potential donors with a history of tuberculosis may be considered on a case-by-case basis only if they have received active treatment for at least 6 months. Donors with latent tuberculosis need active tuberculosis to be ruled out as far as possible and may be considered on a case-by-case basis with ongoing surveillance for the appearance of tuberculosis in the recipient and consideration of recipient tuberculosis prophylaxis. Prophylaxis should also be considered where the donor has a history of latent tuberculosis that has not been sufficiently treated or in the circumstance of unexplained pulmonary apical fibrosis in the donor without cavitation and without additional testing. At this time, IGRA testing in donors is not suggested. Active tuberculosis in the donor needs to be considered and investigated based on clinical and epidemiological features and the decision to proceed to organ transplantation based on the likelihood of active tuberculosis, the results of rapid tests (AFB microscopy and NAT testing from donor samples), and the likelihood of the recipient receiving another donor offer. The location of the infection in the donor is also relevant to the decision to proceed with transplantation and subsequent recipient management, as risk of transmission is lower when the donor infection is at a site other than the allograft (ie, pulmonary tuberculosis in a kidney donor). If donation proceeds, there should be ongoing surveillance for tuberculosis in the recipient and consideration of recipient tuberculosis prophylaxis.
Treatment protocols are informed by drug susceptibility, local drug resistance patterns, and possible drug interactions with immunosuppressant medications (particularly rifampin/rifampicin and rifabutin). A recent systematic review assessed the benefits and harms of antibiotic prophylaxis to prevent tuberculosis in solid organ transplantation, concluding that prophylactic administration of isoniazid reduced the risk of developing tuberculosis posttransplant by more than half (risk ratio (RR), 0.35; 95% confidence interval [CI], 0.14-0.89). There was, however, no significant on all-cause mortality (RR, 1.39; 95% CI, 0.70-2.78), whereas the risk of liver damage was significantly increased (RR, 2.74; 95% CI, 1.22-6.17). The 3 primary studies included in this systematic review were conducted in India and Pakistan:countries with a high prevalence of tuberculosis:therefore, there remains an absence of evidence regarding the benefits and harms of tuberculosis chemoprophylaxis for transplant recipients in area of low tuberculosis prevalence.
When donor-derived, reactivated, or de novo M. tuberculosis infection is suspected in solid organ transplant recipients, clinicians will need to test for disease in the graft as well as other sites, using microscopy, NAT, radiology, pathology (acid-fast bacilli stains), as well as clinical judgment. Notably, the tuberculin skin test and IGRAs have poor sensitivity in immunosuppressed persons after solid-organ transplantation, and in any case are not recommended tests in the diagnosis of active tuberculosis.
In cases where bacterial infections are transferred from donor to recipient, these cases frequently involve resistant bacteria:in particular MRSA, VRE, and multidrug-resistant Gram-negative rods:that were not cleared by standard antibiotic prophylaxis.
Staphylococcus aureus is common in hospital environments, and potential donors may become infected with a resistant strain while in the intensive care unit (ICU). The Australian Group on Antimicrobial Resistance (AGAR) has conducted antimicrobial resistance surveillance since 1986, and surveillance among hospital inpatients since 2005. Laboratories participating in the surveillance network collect S. aureus isolates from hospital inpatients and test then for antimicrobial susceptibility. Epidemiological typing is then performed for isolates identified as MRSA. These surveys have shown a substantial burden of MRSA in Australian hospitals overall, with significant interstate variation in the proportion S. aureus isolates that were MRSA and in the specific MRSA clones circulating in a given region.
In 2011, the proportion of S. aureus isolates that were MRSA was 30.3% nationwide, ranging from 19.9% in Western Australia to 36.8% in New South Wales/ACT. There was wide variation between institutions in the proportion of S. aureus that was MRSA, from 7% to 56%. The overall proportion of S. aureus isolates that were identified as healthcare-associated MRSA was 18.2%, ranging from 4.5% in Western Australia to 28.0% in New South Wales/ACT. In 2011, the predominant hospital-acquired MRSA clone in Australia was ST22-IV [2B] (EMRSA-15), although there was significant interstate variation in the circulating clones and in their susceptibility profile.
Based on the 2011 AGAR survey data, resistance to the non-beta-lactam antimicrobials was common in MRSA isolates, with the exception of fusidic acid, rifampicin, mupirocin, daptomycin, vancomycin and linezolid (resistance levels below 4% nationally). Ceftaroline is also expected to be active.
More recently, the Staphylococcal Sepsis Outcome Program looked at the proportion of S. aureus bacteremia isolates in Australia that are antimicrobial resistant, reporting that 18.8% of S. aureus bacteremia cases were MRSA:a high relatively high proportion compared with several European countries.
Enterococci are among the leading causes of bacteremia, and are intrinsically resistant to a broad range of antimicrobials. Moreover, their ability to acquire resistance through plasmid transfer and transposons has allowed them to rapidly evolve additional resistance in the hospital environment. Although historically enterococcal infections were primarily caused by Enterococcus faecalis, there has been a worldwide increase in nosocomial infections with Enterococcus faecium, which not only is innately resistant to many classes of antibiotics but also extremely good at evolving new antimicrobial resistances.
AGAR commenced the Australian Enterococcal Sepsis Outcome Program (AESOP) in 2011 for the surveillance of E. faecalis and E. faecium bacteremia and to monitor evolving patterns of antimicrobial susceptibility. Of the enterococcal bacteremia cases identified by AESOP in 2014, 54.9% of isolates were E. faecalis and 39.9% were E. faecium. Of the E. faecalis bacteremia cases, 36.5% were hospital-acquired; however, of the E. faecium cases, 71.8% were hospital-acquired. For E. faecalis, acquired resistance was rare with the exceptions of erythromycin (87.4%), tetracycline (72.5%), ciprofloxacin (25.6%), and high-level gentamicin (38.2%). In contrast, the majority of E. faecium isolates were nonsusceptible to multiple antimicrobials, including ampicillin (90%), erythromycin (95%), tetracycline (53%), ciprofloxacin (92%), nitrofurantoin (77%), and high-level gentamicin (62%), and 46.1% were nonsusceptible to vancomycin. By comparison, the population-weighted mean percentage of E. faecium resistant to vancomycin in Europe is 9% (ranging from 0% in Sweden, to 43% in Ireland).
Thus, not only is E. faecium a frequent cause of bacteremia in Australia, the proportion of E. faecium that is resistant to vancomycin is high by international standards. Vancomycin resistance is usually acquired through the acquisition of either the vanA or vanB operon. The first VRE case detected in Australasia occurred in 1994 in a liver transplant patient at Austin Health in Melbourne. Although this first case was a vanA-positive E. faecium, the majority of VRE subsequently detected between 1994 and 2011 was vanB. In late 2013, however, a shift from vanB to vanA E. faecium occurred across Australia. In contrast to the vanB gene, which usually integrates into the E. faecium chromosome, the vanA gene is often located on a plasmid, permitting easy horizontal transfer of resistance. In certain centers dramatic shifts occurred, with vanA almost entirely replacing vanB between 2013 and 2014. A retrospective molecular epidemiological study of VRE among patients admitted to the ICU of Royal Prince Alfred Hospital, Sydney, between January and November 2014 confirmed an increasing incidence of VRE, attributed to multiple concurrent clonal outbreaks of vanA VRE, with reusable medical equipment demonstrated to be an important source of infection. Of 1729 patients admitted over the study period, 5.3% were colonized with VRE on admission (60% with vanB, 39% with vanA, and 1% with both). VRE acquisition rates in the ICU rose from 3.1 per 1000 patient days in 2013 to 7.0 per 1000 patient days in 2014, driven by an increase in vanA acquisition. Overall, 3.6% of patients acquired VRE during their stay in the ICU: 55% acquired vanA VRE, and 45% acquired vanB. The emergence of vanA VRE in Australian hospitals will likely lead to a larger overall burden of VRE in Australia and New Zealand. Recently, the rapid dissemination of novel clone of vanB VRE (ST796) was also reported, first recognized at Austin Health at the beginning of 2012, then almost simultaneously appearing in Auckland, then appearing in South Australia, Tasmania and then New South Wales.
AGAR has been monitoring sepsis due to E. coli and Klebsiella since 1992, with the addition of Enterobacter species to the surveillance program in 2004. The 2014 survey reported moderately high levels of ampicillin/amoxicillin resistance in E. coli isolates (50%), with lower rates of resistance to amoxicillin-clavulanate (8%). Moderate levels of resistance were found in E. coli isolates toward cefazolin (21%) and trimethoprim (29%). Multiresistance is on the rise, particularly in E. coli and E. cloacae isolates, with multiresistance rates of 13% and 12% respectively. Also of concern: approximately 25% of E. coli isolates belonged to the ST131 H30-Rx subclone, which is associated with greater antibiotic resistance and greater virulence.
Klebsiella pneumoniae isolates had higher levels of resistance to piperacillin-tazobactam and ceftazidime compared with E. coli, but lower rates of resistance to amoxicillin-clavulanate, ticarcillin-clavulanate, cefazolin, ceftriaxone, ciprofloxacin, gentamicin, and trimethoprim.
Among Enterobacter species, resistance was common to ticarcillin-clavulanate, piperacillin-tazobactam, ceftriaxone, ceftazidime and trimethoprim. Cefepime, ciprofloxacin, and gentamicin resistance, however, were all less than 10%. In 2014, a total of 14 isolates from 14 patients in 9 institutions across 5 Australian states and territories were found to have a carbapenemase gene. Thus, carbapenem resistance attributable to acquired carbapenemases currently remains uncommon in Australia, although 5 difference gene variants were detected in 2014 (IMP, KPC, VIM, NDM, and OXA-181-like).
Compared with other countries in the region, resistance rates in Gram-negative bacteria in Australia are relatively low, but are similar to those observed in Western Europe.
With the rise of multidrug-resistant bacteria in hospital environments, an increasing number of potential donors are being exposed to multidrug-resistant bacteria in the ICU, which may then be transmitted to recipients by organ transplantation. Of particular concern are VRE, multiresistant Pseudomonas aeruginosa, ESBL-producing enterobacteriaceae, carbapenem-resistant Acinetobacter baumannii, K. pneumoniae, and other carbapenem-resistant enterobacteriaceae. Lanini et al have described the incidence of carbapenem-resistant Gram-negative bacteria in Italian transplant recipients, reporting 0.63 isolates of carbapenem-resistant Gram-negative bacteria per 1000 recipient days (49 isolates from 887 recipients), and that carbapenem resistance was most frequent among Klebsiella spp. isolates (49%). Rates of nosocomial carbapenem-resistant bacterial infection are likely to be higher in Italy than in Australia and New Zealand, given that carbapenemase-producing Enterobacteriaceae are endemic in Italy and are regularly isolated from patients in most hospitals. This study also reported that mortality was 10.23 times higher in recipients who had cultures positive for carbapenem-resistant Gram-negative bacteria after solid organ transplantation compared to those who did not.
Donor-related risk factors for infection or colonization by multidrug-resistant bacteria include prolonged hospital stay (7 days or longer), vasopressor use, and requirement for cardiopulmonary resuscitation or abdominal packing. However, the absence of these risk factors does not preclude nosocomial infection/colonization with multidrug-resistant bacteria, as was demonstrated in a case of carbapenem-resistant A. baumannii transmission from a donor with a hospital stay of only 2 days. In addition, donor country of origin/prior residence is also a potential risk factor: donors from countries with high rates of gut colonization of multidrug-resistant bacteria such as India pose a higher risk of transmission (personal communication L Grayson).
In an Italian study of the incidence and outcomes of transplantation using organs from donors with unknown carbapenem-resistant Gram-negative bacterial infection, 10.5% of organ donors were discovered posttransplant to be infected or colonized with carbapenem-resistant Gram-negative bacteria, with proven transmission to the organ recipient in 13% (4 of 30) of affected transplants. The recipients in whom transmission did occur all received antibiotic therapy that was late, short, or inappropriate. There was also a higher risk of transmission where the donors were bacteremic and the donor organ was culture-positive. The first 2 transmission cases involved a donor who died of cerebrovascular accident after 4 days in the ICU and developed a fever after brain death; the day after organ transplantation the donor's blood cultures became positive for carbapenem-resistant K. pneumoniae. Liver, lungs, and pancreas were donated to 4 recipients. The recipient of an extended right graft of the donor liver received preemptive treatment with meropenem alone for 3 days, starting on day 4 posttransplant. On day 7, samples from abdominal drainage fluid were sent for microbiological testing and cultures were positive for carbapenem-resistant K. pneumoniae. The patient was treated with colistin and tigecycline, and the infection was resolved by day 37 posttransplant. The lung recipient was commenced on meropenem alone on day 2 posttransplant; on day 10, cultures from BAL grew carbapenem-resistant K. pneumonia and colistin was added to the treatment for 14 days. The patient did not develop infection, but was found to be colonized by carbapenem-resistant K pneumoniae initially in the lung and later in the rectum.
The third case identified by the Italian study involved a donor who had experienced several episodes of fever while in the ICU and was found to be positive for carbapenem-resistant K. pneumoniae after organ retrieval and transplantation. The kidney recipient, who received a full, targeted antibiotic treatment regimen (gentamicin and meropenem for 8 days), remained negative for carbapenem-resistant K. pneumoniae; however, the liver recipient, who received only 3 days of full antibiotic treatment (gentamicin and meropenem), developed leukocytosis, pleural effusion and an intra-abdominal collection on day 12 posttransplant. On day 24, the liver recipient developed fever and infection of the abdominal wound; cultures from the wound swabs grew carbapenem-resistant K. pneumoniae. The wound infection was treated with a few days of oral antibiotics, and on day 60, abdominal ultrasound revealed a per-hepatic collection that had to be drained, with the fluid culture testing positive for carbapenem-resistant K. pneumoniae. After complete drainage and antibiotic treatment, the infection was resolved, and the patient was alive and well 18 months posttransplant.
The forth transmission case in this series involved a donor who had been admitted to the ICU for septic cerebral embolization from a methicillin-susceptible S. aureus driveline infection and bacteremia, who subsequently died from cerebral hemorrhage. Known to be a rectal carrier of carbapenem-resistant K. pneumoniae, urine cultures turned positive 2 days after retrieval; however, this information was not properly communicated. One recipient received both kidneys, and on posttransplant day 15 he was readmitted to hospital due to high-grade fever which was confirmed to be due to carbapenem-resistant K. pneumoniae infection of the graft. The patient was treated with meropenem+colistin+tigecyline but blood cultures remained positive so the antibiotic regimen was changed to ertapenem+meropenem+colistin. Despite an initial response, bacteremia returned, and the patient died 2 months later due to persistent carbapenem-resistant K. pneumoniae infection of the graft.
In a case reported from Israel, a donor who was an asymptomatic carrier of carbapenem-resistant K. pneumoniae in the respiratory tract donated kidneys, liver, and lungs to 5 recipients. The donor had been admitted to hospital in a deep coma after a near drowning. After 5 days on mechanical ventilation, he was declared brain dead. Routine BAL taken at the time of organ donation grew carbapenem-resistant K. pneumoniae 2 days after transplantation had taken place, with antibiotic sensitivity limited to gentamicin, colistin, and tigecycline. The recipient of the liver and the 2 kidney recipients did not receive postoperative antibiotic treatment, and none developed infectious complications. The 2 lung recipients both received perioperative antibiotic prophylaxis with piperacillin-tazobactam, and after the donor culture results, both received IV colistin for 5 days. One of the lung recipients developed pneumonia 2 weeks after transplantation; Proteus mirabilis was cultured from sputum samples, and after treatment with IV colistin and ciprofloxacin the patient made a full recovery. The second lung recipient was receiving a second transplant due to cystic fibrosis. On day 19 posttransplant, the patient developed tachypnea and dyspnea, and a new infiltrate in the transplanted lung was revealed by radiography. Given the results of donor cultures, the initial empiric antibiotic therapy with piperacillin-tazobactam was changed to colistin and tigecycline; however, the patient continued to deteriorate. One week later, the patient was hypotensive and oliguric, with decreased consciousness. At this time, blood cultures were positive for carbapenem-resistant K. pneumoniae, with antibiotic sensitivity profile the same as the donor. Treatment was unsuccessful and the patient died 4 weeks later.
In a 2007 case of carbapenem-resistant A.baumannii transmission from a donor to a lung recipient in Brazil, the donor had been in the hospital for only 2 days before procurement, with partial pressure of oxygen/fraction of inspired oxygen greater than 300, normal chest x-ray, and no evidence of bronchial aspiration by bronchoscopy. Perioperative antimicrobial prophylaxis consisted of vancomycin plus cefepime. On day 2 posttransplant, the recipient developed fever, arterial hypotension, and respiratory failure, with a chest x-ray revealing an infiltrate in the lower third of the right hemithorax. The patient was reintubated and norepinephrine infusion was started, and meropenem substituted for cefepime. On the same day, the results of the donor's BAL culture became available, yielding A. baumannii susceptible to ampicillin-sulbactam, meropenem, imipenem, and amikacin; the result for carbapenems was, however, incorrect. Although the recipient's lung function improved, she remained febrile and wound site infection was noted. On day 9 posttransplant, carbapenem-resistant A. baumannii was isolated from the recipient's BAL and from the surgical wound specimen, and IV polymyxin B was substituted for meropenem, and tacrolimus dosage was reduced. By day 29 posttransplant, the patient's serum creatinine had risen to 2.1 mg/dL and the decision was made to stop polymyxin B therapy. Serum creatinine level returned to baseline; however, on day 46, the patient presented with pneumonia and recurrence of infection at the surgical wound; a transbronchial lung biopsy showed coexistence of CMV pneumonia. Resumption of polymyxin B together with inhaled amikacin produced transient improvement, but the fever returned and respiratory function progressively worsened. Empiric amphotericin B therapy was started on day 57 and immunosuppression stopped on day 61; however, the patient died on day 65 posttransplant.