Nefrología Vol. 35 Issue 3 Year 2015
Nefrologia 2015;35:340-3 | doi: 10.1016/j.nefro.2015.02.002

Kidney transplant recipients infected with blaKPC-2-producing Klebsiella pneumoniae

Pacientes trasplantados renales con infección por Klebsiella pneumoniae productora de blaKPC-2


a Renal Transplantation, Hospital Alemán de Buenos Aires, Buenos Aires, Argentina
b Fundación para la Investigación y la Asistencia de la Enfermedad Renal (FINAER), Buenos Aires, Argentina

Gram-negative enterobacteria resistant to carbapenem pose a problem, as this antibiotic is usually used for infections caused by Enterobacteriaceae producing extended spectrum β-lactamases.1Klebsiella pneumoniae carbapenemase (KPC) enzymes are the most common class A carbapenemases.2 We have reported the first cases of blaKPC-2-producing K. pneumoniae (KPC-Kp) in kidney transplant patients in our center.3 We describe the treatment and outcomes of 13 new patients.

This retrospective cohort study was conducted at Hospital Alemán, Buenos Aires, Argentina. In the study period (1/2011–8/2013), 93 renal transplants were performed. Disk diffusion antimicrobial susceptibility tests were performed according to the Clinical and Laboratory Standards Institute guidelines. KPC was screened with double-disk diffusion synergy tests; a disk containing 300-μg phenyl boronic acid and a disk containing 10-μg imipenem, 10-μg meropenem, or 10-μg ertapenem. The modified phenotypic Hodge test was performed for isolates exhibiting reduced susceptibility to imipenem or meropenem on the disk diffusion test. blaKPC-2 was confirmed by PCR with primers KPC-F (5′-ATGTCACTGTATCGCCGTCT-3′) and KPC-R (5′-TTTTCAGAGCCTTACTGCCC-3′), heat-extracted DNA as template. Molecular typing was performed using pulsed-field gel electrophoresis, XbaI restriction enzyme; with strain sequence type 258 clone as reference. Tested antibiotics: ampicillin, ampicillin/sulbactam, amoxicillin/clavulanic acid, cephalothin, piperacillin/tazobactam, cefotaxime, ceftazidime, imipenem, meropenem, ertapenem, gentamicin, amikacin, ciprofloxacin, doxycycline, trimethoprim/sulfamethoxazole, nitrofurantoin, and fosfomycin. Tigecycline susceptibility was tested by disk diffusion (susceptible ≥19mm, intermediate 15–18mm, and resistant ≤14mm). The isolates intermediate or resistant on disk testing were confirmed using MIC plates. Polymyxin B susceptibility was determined with Etest® (bioMérieux, Marcy l’Etoile).

Twenty-five KPC-Kp infectious episodes were documented in 13 renal transplant recipients. Mean age was 55.84±13.84 years, 9 (62%) patients were female, and the most frequent primary kidney diseases were diabetes, polycystic kidney disease. All patients received antibiotic prophylactic therapy and induction therapy; 12/13 (92.3%) with thymoglobulin and 1/13 with basiliximab. Nine (69%) patients had been in the intensive care unit (ICU) within 30 days before their first infection, median time of stay was 4 days (0–66 days). Six (46%) patients showed surgical complications, 10/13 (77%) patients had delayed graft function, 9/13 (69%) patients had a central venous catheter and 8/13 (61%) had a urinary catheter for ≥5 days within 3 months before infection. The median time between transplant and the first infection was 79 (8–902) days. Six (46%) patients had more than two infections, totaling 25 infectious episodes (Table 1).

Table 1.

Patients?? characteristics and outcomes.

Patient  Age, year  Sex  Base disease  Days between transplant and first infection  Agent used in induction therapy  Days in ICU (last 3 months prior to first infection)  Positive blood culture  Central venous catheter  Urinary catheter for ≥5 days  DGF  Complication  Number of infection episodes  Outcome 
48  Male  Polycistic kidney disease  660  Thymoglobulin  No  No  No  Yes  None  Successful 
46  Female  Unknown  902  Thymoglobulin  No  No  No  Yes  None  Successful 
69  Female  Diabetes  295  Thymoglobulin  Yes  Yes  Yes  No  None  Successful 
67  Female  Nephroangioscloris  127  Thymoglobulin  No  No  Yes  No  None  Successful 
62  Male  Diabetes  21  Thymoglobulin  10  Yes  Yes  Yes  Yes  Urinary fistula  Successful 
51  Female  Polycistic kidney disease  79  Thymoglobulin  10  Yes  Yes  Yes  Yes  Fistula and peritonitis  Died 
50  Female  Unknown  20  Thymoglobulin  No  Yes  Yes  Yes  Fluid collection  Died 
74  Male  Amyloidosis  22  Thymoglobulin  No  Yes  Yes  Yes  Urinary fistula  Successful 
66  Male  Nephroangioesclorosis  66  Thymoglobulin  24  Yes  Yes  No  Yes  None  Died 
10  68  Female  Diabetes  Basiliximab  No  Yes  Yes  Yes  Wound dehiscence  Successful 
11  33  Female  Unknown  28  Thymoglobulin  No  Yes  No  No  None  Successful 
12  31  Female  Systemic lupus erythematosus  100  Thymoglobulin  10  Yes  No  No  Yes  Hematoma  Successful 
13  61  Female  Nephroangiosclorosis  626  Thymoglobulin  66  Yes  Yes  Yes  Yes  None  Died 

In all episodes, the site of infection was the urinary tract and some antibiotic had been administered within 30 days before diagnosis; however, in 10/25 (40%) episodes, the blood culture showed positive results. The most frequent antibiotics in which bacteria were susceptible were fosfomycin (68%), tigecycline (56%), and colistin (28%). In 1 case, the organism was not susceptible to any tested antibiotic, and in 3/25 (12%) cases, it was susceptible to one drug. Monotherapy was used in 9/25 (36%) episodes; two drugs were used in 10/25 (40%), three in 5/25 (20%), and four in 1/25 (4%) episodes. Table 2 shows the antibiotics used. Tigecycline, alone or combined, resulted in an unsuccessful outcome. The median treatment time was 21 (14–56) days. Four (31%) patients died as a result of infection.

Table 2.

Infection episodes, susceptibility patterns, treatments and outcomes.

Patient  Infection episode  Colonization before infection  Time from transplant to infection  Susceptibility profile  Treatment  CST MIC (mg/l)  MEM MIC (mg/l)  Duration of treatment (days)  Time from isolation to drug administration (days)  Outcome 
15  Yes  660  FOS TIG  FOS  32.0    21  Reinfection 
16  No  902  FOS TIG CST  FOS  0.5    21  Reinfection 
  17    949  FOS TIG AMK DOX  FOS DOX  16.0    21  Reinfection 
18  Yes  295  TIG FOS CST  TIG FOS  0.25    14  Reinfection 
  19    389  FOS DOX CST  DOX  0.12    14  Reinfection 
  20    437  DOX FOS TIG CST  DOX  0.25  21  Reinfection 
  21    522  DOX FOS CST  FOS DOX  0.25  21  Successful 
22  No  127  FOS CST  FOS CST  0.25    15  Successful 
23  Yes  21  FOS TIG CST  TIG CST  1.0    20  Reinfection 
  24    57  TIG  FOS TIG CST  32.0    18  Reinfection 
  25    85  FOS  FOS  >64    42  Reinfection 
  26    288  DOX  DOX CST MEM  42  Successful 
27  No  79  FOS DOX TIG GEN  MEM  0.12  0.5  43  Patient died 
28  No  20  FOS TIG  TIG  0.12    28  Patient died 
29  No  22  DOX FOS GEN TIG  DOX  16.0  15  Reinfection 
  30    40  FOS GEN TIG  MEM FOS  8.0  25  Reinfection 
  31    82  None  CST  4.0  15  Successful 
32  Yes  230  GEN TIG T-S AMK FOS  MEM CST      20  Patient died 
10  33  No  68  FOS AMK NFT TIG CST  MEM FOS  1.0  0.5  14  Reinfection 
  34    103  FOS DOX CST  MEM FOS CST DOX  1.0  15  Reinfection 
  35    143  AMK NFT  MEM FOS  >4  >8  21  Successful 
11  36  NA  28  DOX FOS GA  MEM DOX    14  Reinfection 
  37    98  DOX FOS GA  DOX MEM FOS  0.12    56  Successful 
12  38  NA  100  TIG CST  TIG MEM CST  0.25  41  Reinfection 
13  39  NA  626  FOS TIG DOX  FOS TIG DOX  8.0  16  40  Patient died 

Discussion: Transplant recipients share risk factors for infections with resistant bacteria.4 In a report describing an outbreak of KPC-Kp in transplant patients, infection rates were 17%, 13%, and 26% in heart, liver, and kidney transplant recipients, respectively.5 In our cases, the infection rate was 16% and strain sequence type 258.

The best treatment for KPC has not been established, and we could not identify a successful treatment. Before obtaining susceptibility, empirical treatment was administered; a frequent reported combination therapy is tigecycline plus colistin, but the empirical use of colistin could contribute to selection of resistant strains.6 We avoided nephrotoxic agents, and took into consideration the drug concentration at the site of infection and potential adverse events. Carbapenem monotherapy has a higher rate of treatment failure compared to combination therapy; moreover, only the combination of meropenem, colistin, and tigecycline is associated with improved survival in patients with blood infections.6 Colistine was successful when the isolate showed resistance to all tested antibiotics. The use of a triple-drug regimen including tigecycline, colistin, and meropenem was linked to a reduced risk of death.7

To prevent the spread of bacteria, measures such as perirectal surveillance swabs, susceptibility tests, use of gowns and gloves, and strict hand hygiene were followed. Also, recipients of kidneys from living donors were transferred from the operating room to a non-intensive setting, or underwent a reduced stay in the ICU. Despite its limitations, this report shows that UTIs caused by KPC-Kp pose a threat to kidney transplant patients.

Bibliography
1.
P. Nordmann,T. Naas,L. Poirel
Global spread of carbapenemase-producing Enterobacteriaceae
.Emerg Infect Dis, 17 (2011), pp. 1791-1798 http://dx.doi.org/10.3201/eid1710.110655
2.
P. Nordmann
Carbapenemase-producing Enterobacteriaceae: overview of a major public health challenge
.Med Mal Infect, 44 (2014), pp. 51-56 http://dx.doi.org/10.1016/j.medmal.2013.11.007
3.
F. Cicora,F. Mos,M. Paz,N.G. Allende,J. Roberti
Infections with blaKPC-2-producing Klebsiella pneumoniae in renal transplant patients: a retrospective study
.Transpl Proc, 45 (2013), pp. 3389-3393
4.
C. Van Delden,E.A. Blumberg
Multidrug resistant gram-negative bacteria in solid organ transplant recipients
.Am J Transplant, 9 (2009), pp. S27-S34 http://dx.doi.org/10.1111/j.1600-6143.2009.02890.x
5.
M.D. Bergamasco,M. Barroso Barbosa,D. de Oliveira Garcia,R. Cipullo,J.M.C. Moreira,C. Baia
Infection with Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae in solid organ transplantation
.Transpl Infect Dis, 14 (2012), pp. 198-205 http://dx.doi.org/10.1111/j.1399-3062.2011.00688.x
6.
G.C. Lee,D.S. Burgess
Treatment of Klebsiella pneumoniae carbapenemase (KPC) infections: a review of published case series and case reports
.Ann Clin Microbiol Antimicrob, 11 (2012), pp. 32 http://dx.doi.org/10.1186/1476-0711-11-32
7.
M. Tumbarello,P. Viale,C. Viscoli,E.M. Trecarichi,F. Tumietto,A. Marchese
Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: importance of combination therapy
.Clin Infect Dis, 55 (2012), pp. 943-950 http://dx.doi.org/10.1093/cid/cis588
The Authors
Órgano Oficial de la Sociedad Española de Nefrología
Contact | Terms and conditions | Privacy policy | Cookies policy