Diarrhea is a common condition after solid organ transplant (SOT); Clostridium difficile-associated colitis (CDAC) is one of the most common infections after SOT. We documented previously that some types of enteritis are associated with an elevation of tacrolimus (TAC) trough concentrations by interfering with the drug's complex metabolism.
Patients and Methods:
Tacrolimus concentrations of 25 SOT recipients including 12 renal and 13 liver recipients before, during, and after CDAC were analyzed retrospectively.
Results:
Median age of the 25 patients was 54 y (range, 36–71), there were 15 males and 10 females. Clostridium difficile-associated colitis developed at a median of 55 d (range 2–4551) post-SOT. Median TAC concentrations prior to the outbreak of CDAC were 6.9 ng/mL (range, <1.5–17.2), 5.6 ng/mL (range, <1.5–13.2) during diarrhea, and 7.4 ng/mL (range, <1.5–24.3) after resolution of diarrhea (p > 0.05, NS). Treatment of CDAC consisted of metronidazole for 14 d in all cases. All patients recovered from CDAC but seven patients had CDAC relapse.
Conclusions:
In contrast to other types of infectious diarrhea such as rotavirus enteritis and cryptosporidiosis, CDAC is not associated with an increase in TAC concentrations. This is because C. difficile causes primarily colitis as opposed to other organisms, which are associated with enteritis.
Get full access to this article
View all access options for this article.
References
1.
StelzmuellerI, GoegeleH, BieblM, et al.Clostridium difficile colitis in solid organ transplantation—A single-center experience. Dig Dis Sci, 2007; 52:3231–3236.
2.
StelzmuellerI, WiesmayrS, SwensonBR, et al.Rotavirus enteritis in solid organ transplant recipients: An underestimated problem?. Transpl Infect Dis, 2007; 9:281–28.
3.
GinsburgPM, ThuluvathPJ. Diarrhea in liver transplant recipients: etiology and management. Liver Transpl, 2005; 11:881–90.
4.
AulagnonF, ScemLaA, DeWolfS, LegendreC, ZuberJ. Diarrhea after kidney transplantation: A new look at a frequent symptom. Transplantation. 2014; 98:806–816.
5.
StelzmuellerI, DunstKM, HengsterP, et al.A cluster of rotavirus enteritis in adult transplant recipients. Transpl Int, 2005; 18:470–474.
6.
WesthoffTH, VergoulidouM, LoddenkemperC, et al.Chronic norovirus infection in renal transplant recipients. Nephrol Dial Transplant, 2009; 24:1051–1053.
7.
AlbrightJB, BonattiH, MendezJ, et al.Early and late onset Clostridium difficile-associated colitis following liver transplantation. Transpl Int, 2007; 20:856–866.
8.
GelladZF, AlexanderBD, LiuJK, et al.Severity of Clostridium difficile-associated diarrhea in solid organ transplant patients. Transpl Infect Dis, 2007; 9:276–280.
9.
KevenK, BasuA, ReL, et al.Clostridium difficile colitis in patients after kidney and pancreas-kidney transplantation. Transpl Infect Dis, 2004; 6:10–14.
10.
ArslanH, InciEK, AzapOK, et al.Etiologic agents of diarrhea in solid organ recipients. Transpl Infect Dis, 2007; 9:270–275.
11.
BobakD, ArfonsLM, CregerRJ, LazarusHM. Clostridium difficile-associated disease in human stem cell transplant recipients: Coming epidemic or false alarm?. Bone Marrow Transplant, 2008; 42:705–713.
12.
GundersonCC, GuptaMR, LopezF, et al.Clostridium difficile colitis in lung transplantation. Transpl Infect Dis, 2008; 10:245–251.
13.
MunozP, GiannellaM, AlcalaL, et al.Clostridium difficile-associated diarrhea in heart transplant recipients: Is hypogammaglobulinemia the answer?. J Heart Lung Transplant, 2007; 26:907–914.
14.
MunozP, PalomoJ, YanezJ, BouzaE. Clinical microbiological case: A heart transplant recipient with diarrhea and abdominal pain. Recurring C. difficile infection. Clin Microbiol Infect, 2001; 7:451–452.
15.
NomuraK, FujimotoY, YamashitaM, t al.Absence of pseudomembranes in Clostridium difficile-associated diarrhea in patients using immunosuppression agents. Scand J Gastroenterol, 2009; 44:74–78.
16.
PerkinsJD. Clostridium difficile colitis associated with other complications following liver transplantation. Liver Transpl, 2008; 14:253–254.
17.
RiddleDJ, DubberkeER. Clostridium difficile infection in solid organ transplant recipients. Curr Opin Organ Transplant, 2008; 13:592–600.
18.
CrossTJ, BerryPA, BurroughsAK. Infection in solid-organ transplant recipients. N Engl J Med, 2008; 358:1302.
19.
KhannaS, MontassierE, SchmidtB, et al.Gut microbiome predictors of treatment response and recurrence in primary Clostridium difficile infection. Aliment Pharmacol Ther, 2016; 44:715–727.
20.
CunninghamR, DialS. Is over-use of proton pump inhibitors fuelling the current epidemic of Clostridium difficile-associated diarrhoea?. J Hosp Infect, 2008; 70:1–6.
21.
StaufferBH, NormanK, Jean-PierreC, et al.Acid blocking medication usage pre and post liver transplantation. Eur Surg, 2007; 39:57–60.
22.
FruhwirthM, FischerH, SimmaB, et al.Rotavirus infection as cause of tacrolimus elevation in solid-organ-transplanted children. Pediatr Transplant, 2001; 5):88–92.
23.
BonattiH, BarrosoLFII, SawyerRG, et al.Cryptosporidium enteritis in solid organ transplant recipients: multicenter retrospective evaluation of 10 cases reveals an association with elevated tacrolimus concentrations. Transpl Infect Dis, 2012; 14:635–648.
24.
BerengueJI, Lopez-EspinosaJA, Ortega-LopezJ, et al.Two- to three-fold increase in blood tacrolimus (FK506) levels during diarrhea in liver-transplanted children. Clin Transplant, 2003; 17:249–253.
25.
McMasterP, MirzaDF, IsmailT, et al.Therapeutic drug monitoring of tacrolimus in clinical transplantation. Ther Drug Monit, 1995; 17:602–605.
26.
BonattiHJR, MetzgerR, SwensonBR, SawyerRG. Solid organ recipients are at increased risk for recurrent Clostridium difficile colitis. Eur Surg, 2014; 46:160–164.
27.
MutoCA, BlankMK, MarshJW, et al.Control of an outbreak of infection with the hypervirulent Clostridium difficile BI strain in a university hospital using a comprehensive “bundle” approach. Clin Infect Dis, 2007; 45:1266–1273.
28.
BhanguS, BhanguA, NightingaleP, MichaelA. Mortality and risk stratification in patients with Clostridium difficile associated diarrhoea colorectal disease. Colorectal Dis, 2010; 12:241–246.
29.
PaudelS, ZacharioudakisIM, ZervouFN, et al.Prevalence of Clostridium difficile infection among solid organ transplant recipients: A meta-analysis of published studies. PLoS One, 2015; 10:e0124483.
30.
AsanoT, NishimotoK, HayakawaM. Increased tacrolimus trough levels in association with severe diarrhea, a case report. Transplant Proc, 2004; 36:2096–2097.
31.
EadesSK, BoineauFG, ChristensenML. Increased tacrolimus levels in a pediatric renal transplant patient attributed to chronic diarrhea. Pediatr Transplant, 2000; 4:63–66.
32.
HochleitnerBW, BosmullerC, NehodaH, et al.Increased tacrolimus levels during diarrhea. Transpl Int, 2001; 14:230–233.
33.
VenkataramananR, SwaminathanA, PrasadT, et al.Clinical pharmacokinetics of tacrolimus. Clin Pharmacokinet, 1995; 29:404–430.
34.
LampenA, ChristiansU, GonschiorAK, et al.Metabolism of the macrolide immunosuppressant, tacrolimus, by the pig gut mucosa in the Ussing chamber. Br J Pharmacol, 1996; 117:1730–1734.
35.
WatanabeY, SatoM, AbeY, et al.Enteric absorption of FK 506: Estimation by a block liver perfusion technique in rats. Transplant Proc, 1998; 30:3777–3778.
36.
KaplanB, LownK, CraigR, et al.Low bioavailability of cyclosporine microemulsion and tacrolimus in a small bowel transplant recipient: Possible relationship to intestinal P-glycoprotein activity. Transplantation, 1999; 67:333–335.
37.
KolarsJC, LownKS, Schmiedlin-RenP, et al.CYP3A gene expression in human gut epithelium. Pharmacogenetics, 1994; 4:247–259.
38.
NovelliM, MuiesanP, Mieli-VerganiG, et al.Oral absorption of tacrolimus in children with intestinal failure due to short or absent small bowel. Transpl Int, 1999; 12:463–465.
39.
ZahirH, McCaughanG, GleesonM, et al.Factors affecting variability in distribution of tacrolimus in liver transplant recipients. Br J Clin Pharmacol, 2004; 57:298–309.
40.
ZahirH, NandRA, BrownKF, et al.Validation of methods to study the distribution and protein binding of tacrolimus in human blood. J Pharmacol Toxicol Methods, 2001; 46:27–35.
41.
Abu-ElmagdK, FungJJ, AlessianiM, et al.The effect of graft function on FK506 plasma levels, dosages, and renal function, with particular reference to the liver. Transplantation, 1991; 52:71–77.
42.
BekerskyI, DresslerD, AlakA, et al.Comparative tacrolimus pharmacokinetics: Normal versus mildly hepatically impaired subjects. J Clin Pharmacol, 2001; 41:628–635.
43.
JainAB, VenkataramananR, CadoffE, et al.Effect of hepatic dysfunction and T tube clamping on FK 506 pharmacokinetics and trough concentrations. Transplant Proc, 1990; 22:57–59.
44.
StelzmuellerI, WiesmayrS, EllerM, et al.Enterocolitis due to simultaneous infection with rotavirus and Clostridium difficile in adult and pediatric solid organ transplantation. J Gastrointest Surg, 2007; 11:911–917.
45.
BurdeseM, VeglioV, ConsiglioV, et al.A dance teacher with kidney-pancreas transplant and diarrhoea: What is the cause?. Nephrol Dial Transplant, 2005; 20:1759–1761.
46.
DelisSG, TectorJ, KatoT, et al.Diagnosis and treatment of cryptosporidium infection in intestinal transplant recipients. Transplant Proc, 2002; 34:951–952.
