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Invasive bacterial infections have become a leading cause tance to broad-spectrum antibiotics including b-lactams,
of morbidity and mortality among solid organ transplant aminoglycosides, £uoroquinolones, and tetracyclines.
(SOT) recipients (1). Notably, the emergence of multi-drug Most notably, carbapenem-resistant A. baumannii (CRAB)
resistant (MDR) gram-negative bacteria among SOT recip- has emerged with the acquisition of enzymes (e.g., metallo-
ients has been associated with an increased risk of allograft b-lactamases, oxacillinases) capable of hydrolyzing imipe-
loss (2). Outcomes among transplant recipients with infec- nem. This recent rise in MDR A. baumannii infections has
tion due to extended-spectrum beta-lactamase (ESBL)- been associated with longer hospital length of stay (5) and
producing Enterobacteriaceae or MDR Pseudomonas aeru- increased patient mortality (6).
ginosa have been described previously (2, 3). Despite a national rise in carbapenem resistance among
Acinetobacter baumannii is almost exclusively a no- A. baumannii (National Nosocomial Infections Surveil-
socomial pathogen, associated with soft tissue infection, lance System, unpublished data), outcomes among SOT re-
urinary tract infection (UTI), catheter-associated blood- cipients who acquire this pathogen are largely unknown.
stream infection (BSI), and ventilator-associated pneumo- We report the clinical features and outcomes of abdominal
nia (VAP) among critically ill patients (4). Already organ transplant recipients who acquired CRAB in the
equipped with intrinsic resistance to the aminopenicillins post-transplant period.
and ¢rst- and second-generation cephalosporins, A. bau-
mannii has gained recent notoriety with its acquired resis-
Abbreviations : BSI, bloodstream infection; CRAB, carbapenem-resistant
Acinetobacter baumannii; ERCP, endoscopic retrograde cholangiopancreatography; Methods
ESBL, extended-spectrum beta-lactamase; HCV, hepatitis C virus; ICU, intensive
care unit; MDR, multi-drug resistant; MRSA, methicillin-resistant Staphylococcus
aureus; PTD, post-transplant day; SOT, solid organ transplant; UTI, urinary tract
infection; VAP, ventilator-associated pneumonia; VRE, vancomycin-resistant Northwestern Memorial Hospital (NMH) is an 825 -bed ac-
Enterococcus ademic medical center in Chicago, Illinois. From January 1,
87
Reddy et al: Acinetobacter infections after organ transplant
2004 to December 31, 2005, 794 abdominal organ trans- lished criteria were used to de¢ne clinical infection (8).
plants were performed at NMH including 172 liver, 407 kid- Summary statistics were performed using SAS software,
ney, and 57 combined liver^kidney procedures.W|thin this version 9.1 (SAS Institute). When appropriate, categorical
time frame, all patients with a positive culture for CRAB variables were compared using Fisher’s exact test.
were identi¢ed through the electronic microbiology da-
tabase. Organ recipients who acquired CRAB during the
study period were considered for analysis. Study patients
A. baumannii isolates were identi¢ed by the semi-auto-
mated VITEK 2s system (bioMe¤ rieux, Marcy l’Etoile,
France). Further standard biochemical techniques for the During the study period, 248 patients with A. baumannii
identi¢cation of Acinetobacter were performed if automated were identi¢ed. Among abdominal organ transplant recip-
results were o90% accurate. Carbapenem resistance was ients with A. baumannii (n 5 14), 6 (42.9%) acquired a
de¢ned as a minimum inhibitory concentration of imipe- carbapenem-resistant isolate. In contrast, among
nem 16 mg/mL. Routine antimicrobial susceptibility non-transplant patients with A. baumannii (n 5 234), only
testing for gentamicin, tobramycin, ampicillin^sulbactam, 32 (13.7%) patients acquired a carbapenem-resistant isolate
imipenem, ceftazidime, aztreonam, cefepime, cipro£oxa- (odds ratio 4.73, 95% con¢dence interval 1.35^16.38,
cin, and trimethoprim^sulfamethoxazole was performed P 5 0.01). Of note, case patients were accrued during a mul-
by the VITEK 2 s system. Additional susceptibility testing ti-city CRAB outbreak that occurred within the study pe-
for amikacin, piperacillin^tazobactam, minocycline, tetra- riod (9). Table 1 summarizes the important clinical,
cycline, and doxycycline was performed by the Kirby^Bau- epidemiologic, and transplant features of the 6 recipients
er disk di¡usion method and isolates were characterized as who acquired CRAB.
resistant or susceptible based on the interpretative criteria
of the Clinical Laboratory Standards Institute (7 ). Suscep-
tibility to colistin was determined by use of the E-test s Case 1
(AB Biodisk, Solna, Sweden).
During the study period, the predominant immunosup- A 61-year-old man with hepatitis B cirrhosis underwent or-
pression protocols for liver transplantation di¡ered by un- thotopic liver transplantation complicated by bile leak and
derlying disease. For hepatitis C virus (HCV) infection or ampullary stenosis early in the postoperative course. In-
hepatocellular carcinoma, the preferred regimen included terventions included re-operation and endoscopic retro-
methylprednisolone 500 mg on post-transplant day (PTD) grade cholangiopancreatography (ERCP) with biliary
0 followed by a steroid taper over 10 days. Maintenance of stent placement. After an extended intensive care unit
immunosuppression included tacrolimus (Prografs, (ICU) stay for ventilatory failure and prolonged mechanical
Fujisawa Pharmaceuticals, Deer¢eld, Illinois, USA) admin- ventilation, the patient was discharged to a subacute nurs-
istered to achieve a 12-h blood level of 8 ng/mL for deceased- ing facility. On PTD 45, the patient was re-admitted with
donor transplants or 5^8 ng/mL for living-donor trans- sepsis. He underwent ERCP, biliary traction sphincter-
plants for the initial 3 months post transplant. Other liver otomy, balloon dilation of the choledochocholedochostomy
recipients and combined organ recipients received anastamotic stricture, and biliary stent replacement.
alemtuzumab 30 mg as induction therapy and methylpred- Post-transplant course was further complicated by car-
nisolone 500 mg on PTD 0, 250 mg on PTD 1, and 125 mg on bapenem-sensitive A. baumannii urinary and respiratory
PTD 2. Tacrolimus was administered to achieve 12-h blood tract infections and subsequently, invasive pulmonary
concentrations of 8^10 ng/mL for the ¢rst 3 months post aspergillosis. On PTD 89, the patient developed CRAB
transplant. Combined organ recipients also received my- VAP. CRAB-directed antimicrobial therapy with amp-
cophenolate mofetil (Cellcepts, Roche, Nutely, New Jersey, icillin^sulbactam, amikacin, and nebulized tobramycin
USA) at target dose of 1.5^2.0 g/day. was administered. The pneumonia resolved and he was
The kidney recipient in this case series was infected with discharged on PTD 103.
HCV and received induction basiliximab 20 mg on PTD 0
and 2, methylprednisolone 500 mg on PTD 0, mycopheno- Case 2
late mofetil 1.0 g/day, and tacrolimus to achieve 12-h blood
concentrations of 8^10 ng/mL. A 66 -year-old woman with end-stage liver disease due to
Medical records were reviewed to collect data on patient non-alcoholic steatotic liver disease and hepatorenal syn-
demographics, transplant history, immunosuppressant drome underwent combined liver and kidney transplanta-
use, co-morbid conditions, and clinical presentation, com- tion. The immediate postoperative course was complicated
plications, and outcomes associated with CRAB. Estab- by a retroperitoneal hematoma and delayed renal allograft
Clinical and epidemiologic features of organ recipients colonized or infected with carbapenem-resistant Acinetobacter baumannii (CRAB)
Case
Characteristics 1 2 3 4 5 6
NASH, non-alcoholic steatotic hepatitis; HCC, hepatocellular carcinoma; HRS, hepatorenal syndrome; FSGS, focal segmental glomerulosclerosis; TAC,
tacrolimus; MMF, mycophenolate mofetil; BL, beta lactam; BLI, beta-lactamase inhibitor; PNA, pneumonia; UTI, urinary tract infection; BSI, bloodstream
infection; SSI, surgical site infection; DGF, delayed renal allograft function; N/A, not applicable; UA, unavailable; MELD, model for end-stage liver disease; IS,
immunosuppression; VRE, vancomycin-resistant Enterococcus; HSV, herpes simplex virus; 41, fourth generation; CoNS, coagulase-negative
Staphylococcus.
Table1
function secondary to acute tubular necrosis. On PTD 20, sistent ascites, prolonged lymphopenia, and renal allograft
the patient was diagnosed with a Klebsiella pneumoniae dysfunction requiring hemodialysis. Antibiotic therapy
UTI and Candida peritonitis, treated with piperacillin^ta- was administered for urinary, respiratory, and BSI due to
zobactam and £uconazole, respectively. The patient re- an ESBL-producing K. pneumoniae. The patient was re-
turned to the hospital on PTD 54 with fevers, ascites, and hospitalized on PTD 214 with K. pneumoniae, Proteus mira-
declining renal function. Over the next month, her hospital bilis, and vancomycin-resistant Enterococcus faecium (VRE)
course was marked by respiratory failure with prolonged urosepsis and hydronephrosis of the allograft necessitat-
mechanical ventilation and tracheostomy placement, per- ing nephrostomy tube placement. Renal allograft biopsy
suggested rejection. Computed tomography of the chest sistant Staphylococcus aureus (MRSA) BSI, and Escherichia
demonstrated bibasilar consolidation. Despite aggressive coli UTI. Though CRAB was isolated from a respiratory
supportive measures, the patient su¡ered from cardiopul- tract culture, there was no evidence of pneumonia. The pa-
monary arrest and anoxic brain injury, expiring on PTD tient clinically improved without CRAB-directed antimi-
219. Respiratory cultures later identi¢ed CRAB and MDR crobial therapy and was discharged in stable condition on
P. aeruginosa. PTD 125. She subsequently died at an outside hospital on
PTD 162. Her death was attributed to sepsis, but the etio-
logic agent was not identi¢ed.
Case 3
ment. Numerous hospital admissions for UTIs and persis- graft rejection (n 5 2), and ureteral stenosis with urinary
tent abdominal wound infection followed over the next 2 leak and urinoma.
months. Delayed graft function persisted, and when a renal All 6 patients had risk factors for colonization and/or in-
biopsy on PTD 129 indicated moderate cellular rejection, fection with an MDR pathogen (11, 12). In the 30 days before
the patient received methylprednisolone. On PTD 193, CRAB identi¢cation, all were exposed to a subacute nurs-
CRAB was isolated from the abdominal wound and the ing facility and 5 (83%) patients were in the ICU. All 6 pa-
bloodstream. Tobramycin and colistin were initiated. Ulti- tients were colonized or infected with another MDR
mately, ongoing abdominal infection prompted transplant organism including MRSA, VRE, ESBL-producing Enter-
nephrectomy. Multiple infectious complications followed, obacteriaceae, or MDR P. aeruginosa. In addition, all 6 pa-
including VAP and parapneumonic empyema with MDR tients had a central venous catheter, 4 (66.7%) required
P. aeruginosa and CRAB, and cytomegalovirus syndrome. mechanical ventilation, and 3 (50%) required renal replace-
Despite aggressive antibiotic therapy, the patient died due ment therapy before CRAB acquisition. All patients re-
to sepsis on PTD 217. ceived broad-spectrum antibiotic therapy, including
anaerobic coverage. Details of antecedent antibiotic use
are noted in Table 1. Speci¢cally, carbapenem was used in
Results 4 (66.7%), cephalosporin in 1 (16.7%), vancomycin in 4
(66.7%), metronidazole in 2 (33.3%), and extended spec-
trum b-lactam/ESBL inhibitors in 3 (50%).
Our cohort included 1 deceased-donor kidney, 1 orthotopic CRAB was acquired a median of 93.5 days after trans-
liver, and 4 simultaneous liver^kidney recipients. Recipi- plantation (range 17^218 days). Most patients (83%) suf-
ents were predominantly male (66.7%) and Caucasian fered from CRAB pneumonia, and half of these recipients
(66.7%) with a median age of 61.5 years (range 35^68 subsequently developed CRAB BSI. Additional sites of
years). Cytomegalovirus donor (D)/recipient (R) serostatus CRAB infection included the urinary tract and the surgical
included 2 (33.3%) D 1 /R , 2 (33.3%) D 1 /R 1 , and 2 site. A sixth patient was colonized, but not infected, with
(33.3%) D /R 1 . Five isolates were typed; 4 (cases 2, 3, 5, the organism.
and 6) resembled the isolate involved in the citywide out- Four (80%) of 5 infected patients received antimicrobial
break. therapy for CRAB while 1 patient died before the identi¢ca-
All 6 recipients developed signi¢cant surgical and medi- tion of CRAB. Details of therapy are outlined inTable 2. All
cal post-transplant complications before the acquisition of 4 patients were treated with a multi-drug regimen: 2 pa-
CRAB. Hepatic complications included bile leak (n 5 2), tients received ampicillin^sulbactam in combination with
ampullary stenosis, ischemic cholangiopathy (n 5 2), and an aminoglycoside (1 of whom received tigecycline) while
hepatic allograft dysfunction. Complications of kidney the other 2 were treated with colistin and tigecycline alone.
transplantation included post-transplant hematoma Subsequent to CRAB acquisition, all patients had poor
(n 5 2), delayed renal allograft function (n 5 4), renal allo- outcomes. Four kidney recipients su¡ered from graft fail-
Carbapenem-resistant Acinetobacter baumannii (CRAB): site of infection, antibiotic susceptibilities, and antibiotic management
Case Transplant CRAB source AMP-S IMIP CIP DOXY COL TET AMIK TOB Antibiotic therapy
OLT, orthotopic liver transplant; CRT, deceased donor kidney transplant; PNA, pneumonia; UTI, urinary tract infection; BSI, bloodstream infection; SSI, skin
and soft tissue infection; ND, not done; S, susceptible by Kirby^Bauer; R, resistant by Kirby^Bauer; AMP-S, ampicillin^sulbactam; IMIP, imipenem; CIP,
cipro£oxacin; DOXY, doxycycline; COL, colistin;TET, tetracycline; AMIK, amikacin;TOB, tobramycin;TIG, tigecycline; PIP, piperacillin; RX, therapy.
Table 2
ure requiring renal replacement therapy and 1 liver^kidney ins, and extended spectrum b-lactam/ESBL inhibitors (11,
recipient experienced hepatic dysfunction. Renal allograft 17^19). Among 6 lung transplant recipients with MDR A.
rejection occurred in 2 recipients. The kidney recipient un- baumannii, antecedent mechanical ventilation and broad-
derwent transplant nephrectomy in an unsuccessful at- spectrum antibiotic exposure were common characteris-
tempt to control CRAB infection. Despite multi-drug tics (16).
therapy, 4 (66.7%) patients died subsequent to CRAB diag- Case patients had established risk factors for coloniza-
nosis, with CRAB a primary or contributing factor to death. tion and infection with MDR bacteria after SOT. Several
A ¢fth patient died from sepsis of unclear etiology. All studies have demonstrated that biliary complications or
deaths occurred within the ¢rst year post transplant, with the need for re-operation are associated withVRE coloniza-
median of 162 days (range 53^219 days). T|me from CRAB tion and infection after liver transplantation (20, 21). Nota-
acquisition to infection-related death among these 5 pa- bly, ischemic injury and other biliary complications
tients was a median of only 36 days (range 1^71 days). occurred among 3 liver transplant recipients in the present
study. Among renal transplant recipients, Linares et al. (2,
22) found that post-transplant urinary obstruction, post-
transplant nephrostomy, and a post-transplant hemodialy-
Discussion sis requirement are risk factors for the acquisition of anti-
biotic-resistant bacteria for kidney recipients. Four of 5
kidney recipients in the present study su¡ered from de-
MDR A. baumannii infections are associated with mortal- layed graft function and a post-transplant hemodialysis
ity rates of 16^49% among hospitalized patients (5, 6, 13). requirement, supporting these ¢ndings. Surgical interven-
However, outcomes of transplant recipients infected with tion was common among cases patients; 66.7% of patients
MDR A. baumannii infections are not well de¢ned. We re- colonized or infected with CRAB underwent re-operation
port our center’s recent experience with CRAB infections post transplantation.
among liver and/or kidney transplant recipients. Another common characteristic of this small cohort in-
Singh et al. (14) noted that liver transplant recipients in- cluded the use of alemtuzumab induction immunosuppres-
fected with an MDR organism are signi¢cantly less likely sion. Alemtuzumab results in profound and prolonged
to survive at 1 year compared to non-infected liver trans- immunosuppressive e¡ects but its association with the
plant counterparts or to those infected with susceptible development of MDR bacterial infections remains unclear
pathogens (14). Our cohort had similar poor outcomes, in- (23). Our cohort suggests that further study is required
cluding 66.7% renal allograft loss, 66.7% CRAB-related to clarify the risk of bacterial infection with this agent.
mortality, and 80% overall infection-related mortality Optimal therapies for the treatment of CRAB infections
within the ¢rst year of transplantation. In a retrospective are not well de¢ned. Among immunocompetent patients
study of Acinetobacter infections among critically ill surgi- with a sulbactam-susceptible Acinetobacter isolate, mono-
cal patients, the reported mortality in the organ transplant therapy with sulbactam was as e¡ective as imipenem in
subset (n 5 30) was 64.5%. Immunosuppression, primarily the treatment of VAP (24) and BSI (25). In the present study,
as a result of organ transplantation, was predictive of poor sulbactam therapy was only administered in conjunction
outcomes. While carbapenem resistance was prevalent in with an aminoglycoside, doxycycline and/or tigecycline
this cohort, it is unclear what proportion of the transplant (see Table 2); 1 patient survived and 1 died. Uncontrolled
recipients had MDR A. baumannii (15). Among the ¢rst to studies suggest that the use of colistin in combination with
examine this emerging pathogen in immunocompromised other antimicrobials (including cabapenems, ampicillin^
hosts, Sopirala et al. (16) found that lung transplant recipi- sulbactam, aminoglycosides, and rifampin) may have some
ents with MDR A. baumannii infection su¡er from allo- success in the treatment of VAP due to MDR A. baumannii
graft rejection (66.7%) or even death (33.3%). (26, 27 ). T|gecycline, a glycylcycline derivative of tetracy-
Risk factors for MDR A. baumannii acquisition among cline, has demonstrated success in the treatment of CRAB
immunocompetent patients are well de¢ned (11, 12). The infections (28), however, its utility in the treatment of seri-
present study suggests that such characteristics as central ous infection or BSI remains unclear (29). Patients in this
venous catheter use, prolonged ICU stay, and mechanical study who received colistin and/or tigecycline died, demon-
ventilation are also associated with CRAB acquisition and strating the need for further study of these agents in the
infection among SOT recipients. Baran et al. (11) noted that SOT population.
patients who received prior antibiotic therapy were at In summary, our experience suggests that poor allograft
5 -fold greater risk of CRAB. Not surprisingly, all patients outcomes and high mortality occur in patients who acquire
in this study were exposed to antimicrobial agents known CRAB in the early post-transplant period. In most cases,
to predispose to CRAB, such as carbapenems, cephalospor- CRAB infection was directly implicated in or at least con-
tributed to mortality.Though this report is limited by small 13. Kuo LC, Lai CC, Liao CH, et al. Multidrug-resistant Acinetobacter
cohort size and retrospective data collection, common fea- baumannii bacteremia: clinical features, antimicrobial therapy and
tures among this cohort included receipt of combined or- outcome. Clin Microbiol Infect 2007; 13 (2): 196^198.
14. Singh N, Gayowski T, Rihs JD,Wagener MM, Marino IR. Evolving
gan transplants, alemtuzumab induction, technical trends in multiple antibiotic-resistant bacteria in liver transplant
complications, and prior infection with other antimicrobi- recipients: a longitudinal study of antimicrobial susceptibility
al-resistant pathogens. Further study is required to de¢ne patterns. Liver Transplant 2001; 7 (1): 22^26.
acquisition risk factors speci¢c to organ recipients. 15. Trottier V, Namias N, Pust DG, et al. Outcomes of Acinetobacter
baumannii infection in critically ill surgical patients. Surg Infect
(Larchmt) 2007; 8 (4): 437^443.
16. Sopirala MM, Pope-Harman A, Nunley DR, Mo¡att-Bruce S, Ross P,
Acknowledgements: Martin SI. Multidrug resistant Acinetobacter baumannii pneumonia in
lung transplant recipients. J Heart LungTransplant 2008; 27 (7): 804^807.
Funding source: Northwestern University Feinberg School 17. del Mar Tomas M, Cartelle M, Pertega S, et al. Hospital outbreak
caused by a carbapenem-resistant strain of Acinetobacter baumannii:
of Medicine. patient prognosis and risk factors for colonization and infection. Clin
Potential con£icts of interest: None. Microbiol Infect 2005; 11: 540^546.
18. Kim YA, Choi JY, Kim CK, et al. Risk factors and outcomes of blood-
stream infections with metallo-b-lactamase-producing Actinetobacter.
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