Pneumocystis pneumonia in solid organ transplant recipients: not yet an infection of the past.

BACKGROUND: Solid organ transplant (SOT) recipients are at risk for Pneumocystis pneumonia (PCP), especially in the first year post transplant. Although trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis substantially decreases this risk, there is little data or consensus on optimal duration of prophylaxis. Consequently, there is lack of standardization of prophylaxis duration (3 months to lifelong, depending on organ group) in SOT programs. METHODS: We performed a retrospective chart review of all cases of confirmed PCP, in adult kidney, pancreas, liver, and lung transplant recipients from 2001 to 2011 in our SOT program. RESULTS: Of 1241 patients followed in our clinic (657 kidney, 44 kidney/pancreas, 436 liver, and 104 lung or heart/lung), a total of 14 PCP cases were identified in 2 kidney, 1 kidney/pancreas, 5 liver, 5 single lung, and 1 heart/lung transplant recipient. At the time of PCP diagnosis, immunosuppression in most cases consisted of prednisone, tacrolimus, and mycophenolate mofetil (79% of patients), and 53% had previously received TMP-SMX for prophylaxis. None were on PCP prophylaxis at the time of illness onset. PCP occurred early in all 5 liver transplant recipients and in 1 kidney transplant recipient, none of whom had ever received prophylaxis (17-204 days post transplant). Of those who had received 6 months of prophylaxis (1 kidney, 1 kidney/pancreas), PCP occurred at 846 and 4778 days, respectively. Late onset PCP occurred in lung recipients who had received 12 months of prophylaxis (lung 645-1414 days, heart/lung 1583 days post transplant). Five patients had experienced acute rejection and 6 patients had cytomegalovirus (CMV) viremia on average 59 and 204 days preceding PCP, respectively. Three deaths (1 liver, 2 lung) were thought to be directly related to complications of PCP. CONCLUSION: Our experience with late PCP cases in lung transplant recipients receiving only 1 year of prophylaxis lends support to prolonged PCP prophylaxis in this group. Given the number of patients who had experienced an acute rejection episode or CMV disease preceding PCP in non-lung SOT recipients, consideration should be given to re-institution of PCP prophylaxis for a period of time after these events in kidney, kidney/pancreas, and liver transplant recipients.

The use of infliximab for treatment of hospitalized patients with acute severe ulcerative colitis.

BACKGROUND/AIM: The use of infliximab in severe ulcerative colitis (UC) is established; however, its role in severe acute UC requires clarification. The present multicentre case series evaluated infliximab in hospitalized patients with steroid-refractory severe UC. METHODS: Patients from six hospitals were retrospectively evaluated. Data collection included demographics, duration of disease and previous treatments. The primary end point was response to in-hospital infliximab; defined as discharge without colectomy. RESULTS: Twenty-one patients (median age 26 years) were admitted between May 2006 and May 2008 with severe UC requiring intravenous steroids and given infliximab (median time to infusion eight days). Sixteen (76%) patients were discharged home without colectomy; three of these underwent colectomy at a later date. Of the remaining 13 patients (62%), all but two did not require further courses of steroids; six patients had infliximab as a bridge to azathioprine and seven patients were maintained on regular infliximab. Five patients required in-hospital colectomy after the initial infliximab. CONCLUSIONS: In this real-life experience of infliximab in patients with steroid-refractory severe UC, infliximab appears to be a viable rescue therapy. The majority of patients were discharged without surgery and 62% maintained response either as a bridge to azathioprine or maintenance infliximab.

Review article: possible beneficial effects of coffee on liver disease and function.

BACKGROUND: Coffee is consumed by 50 percent of Americans every day. After oil, coffee is the second most valuable commodity in the world. In recent years a number of studies have suggested potential health risks associated with coffee consumption; however, the results are controversial. Whilst coffee has been reported to increase cardiovascular risk factors, other investigators have demonstrated its protective effects on diseases ranging from type 2 diabetes to Parkinson's disease. A number of investigators have focused their attention on the relationship between the consumption of coffee and liver disease. AIM: To examine the published literature to date in an attempt to establish the presence of an hepatoprotective effect of coffee. METHODS: Using PubMed, we identified published studies and review articles relating to the effect of coffee consumption on diseases of the liver. CONCLUSION: A number of studies have reported the beneficial effects of coffee on abnormal liver biochemistry, cirrhosis and hepatocellular carcinoma. At the present time the mechanism of this effect remains unclear as does the ''dose'' required to achieve these benefits.

A limited sampling strategy for cyclosporine area under the curve monitoring in lung transplant recipients.

We developed a limited sampling strategy (LSS) for predicting cyclosporine (Neoral) area under the curve from concentration-time data obtained specifically from lung transplant recipients. The optimal and most clinically convenient LSS for lung transplant recipients, based on patient wait time, number of blood samples required, percent prediction error, and assessment of predictive performance is one that requires 2 blood samples collected at 1 and 3 hours post-dose: AUC = 1.75 x C(1) + 4.91 x C(3) + 185.62.

A study of the pharmacokinetic profile of low-dose hepatitis B immune globulin in long-term liver transplant recipients for chronic hepatitis B infection.

Post-transplant protocols for hepatitis B (HBV) prophylaxis using high-dose intravenous hepatitis B immune globulin (10,000 IU) with or without lamivudine are commonly reported. Our centre has previously reported a low-dose intramuscular (i.m.) protocol and lamivudine with excellent results. There have been, however, no pharmacokinetic studies of i.m. hepatitis B immune globulin (HBIG) in this setting. The objective of this study was to determine the pharmacokinetic profile of i.m. HBIG in long-term post-liver-transplant recipients to determine a rational dosing protocol. Six stable liver transplant recipients receiving monthly i.m. HBIG injections for greater than one year were enrolled in this study. All patients had no detectable HBV DNA levels. HBIG titers (anti-HBs) were measured predose, then three times weekly for four weeks and then twice weekly until the serum HBIG titers were 100 IU/L or less. The pharmacokinetic parameters were calculated using noncompartment methods. The mean time to maximum concentration was 10.5 d (range 4-20 d) and the mean half-life was 20 d (range 13.5-23.5 d). Based on these pharmacokinetic parameters in stable long-term post-transplant patients, a rational dosing protocol was developed that allows for more appropriate utility of HBIG and improved patient convenience.

Liver transplantation for chronic hepatitis B infection with the use of combination lamivudine and low-dose hepatitis B immune globulin.

Current protocols for prophylaxis against allograft reinfection after liver transplantation for chronic hepatitis B virus (HBV) infection include the administration of large doses of hepatitis B immune globulin (HBIG), with considerable associated economic costs. Monotherapeutic prophylaxis with lamivudine has been complicated by the development of resistant strains of HBV. We studied the effectiveness of a posttransplantation prophylaxis protocol using combination lamivudine and low-dose HBIG in 7 consecutive patients with chronic HBV infection, 4 of whom were serum HBV DNA positive before pretransplantation lamivudine therapy. All patients were serum HBV DNA negative at transplantation and received lamivudine, 100 mg/d, posttransplantation. HBIG, 2170 IU, was administered intramuscularly intraoperatively and daily for 14 days. Maintenance HBIG therapy consisted of 2170 IU intramuscularly twice weekly, tapered to every 2 to 4 weeks by 12 months posttransplantation. Target serum HBIG (HBV surface antibody) titers were less than 500 IU/L for 6 months, then greater than 300 IU/L until 12 months posttransplantation. Induction serum HBIG titers were determined daily in 5 patients, and both serum HBIG and hepatitis B surface antigen were determined every 4 weeks in all patients. One patient died 61 days posttransplantation; the surviving patients (n = 6) were followed up for a mean of 532 days (range, 395 to 648 days). No patient has developed allograft reinfection. In the induction period, a target HBIG titer of greater than 500 IU/L was not achieved until a mean of 6.8 days (range, 5 to 10 days). In the maintenance period, all patients achieved the target HBIG titer. This suggests combination lamivudine and low-dose HBIG is effective in preventing allograft reinfection by HBV.

Racial differences between solid organ transplant donors and recipients in British Columbia: a five-year retrospective analysis.

BACKGROUND: We attempted to determine whether significant racial differences exist between organ donors and transplant recipients in British Columbia, and whether differences exist between individual organ transplant programs (lung, heart, kidney, liver, and pancreas). The design of the study was a retrospective review. METHODS: We used the database of the British Columbia Transplant Society, a provincial agency, for the years 1992 to 1997 inclusive. The outcome measures were a comparison of racial characteristics of organ donors and transplant recipients collectively and by individual organ transplant program. RESULTS: There were 236 organ donors and 766 transplant recipients. Comparing racial groups between donors and recipients, Caucasians contributed the most donors (93.2%) but received proportionately fewer organs (73.4%, P<0.000001). Orientals donated 3.4% of all organs but constituted 14.4% of all recipients (P<0.00001). Non-Oriental, non-Caucasians (predominantly Asian Indians and Native Aboriginals) constituted 3.4% of all donors and 12.2% of all recipients (P=0.0001). Among the individual organ transplant programs, lung, heart, and pancreas recipients were predominantly Caucasian (148 of 156 recipients). Oriental recipients were more likely to be kidney recipients (19.8% of all kidney recipients) compared with all Oriental recipients (P<0.000001). Likewise, Asian Indians were more likely to be kidney recipients (7.2% of all kidney recipients) compared with all Asian Indian recipients (P<0.0001). Native Aboriginals, however, were more likely to be liver allograft recipients (8.3% of all liver transplants) than nonliver allograft recipients (P=0.017). CONCLUSIONS: In British Columbia, disparity exists between Oriental and non-Oriental, non-Caucasian donors and recipients. Orientals and Asian Indians were more likely to be kidney graft recipients than nonkidney graft recipients, whereas Native Aboriginal recipients seemed more likely to have undergone liver transplantation.

Primary induction with mycophenolate mofetil and corticosteroids in a liver transplant recipient with hepatorenal syndrome.

OBJECTIVE: To report the use of mycophenolate mofetil for primary induction in a liver transplant recipient to avoid the nephrotoxicity of cyclosporine/tacrolimus. CASE SUMMARY: A 47-year-old white man in a hepatic coma with anuric hepatorenal syndrome received a liver transplant, and was given mycophenolate mofetil and corticosteroids as primary induction immunosuppression with the addition of low-dose cyclosporine 13 days later. His renal function improved and he remains rejection-free after 13 months of follow-up. CONCLUSIONS: This case suggests that mycophenolate mofetil may be used as a primary induction agent in liver transplant recipients with renal failure to avoid the additional nephrotoxicity of the standard immunosuppressants, cyclosporine and tacrolimus. Low-dose cyclosporine/tacrolimus may be introduced later as the renal function improves.

Investigation of a possible interaction between ciprofloxacin and cyclosporine in renal transplant patients.

BACKGROUND: Bacterial infection is a common complication during the first few months after renal transplantation. Ciprofloxacin, a fluoroquinolone broad-spectrum antibiotic, is used frequently in treating infections in the early posttransplant period. Evidence from in vitro studies has suggested that ciprofloxacin can antagonize the cyclosporine (CsA)-dependent inhibition of interleukin-2 production. Such an effect in renal transplant patients could antagonize the immunosuppressive activity of CsA and lead to rejection of the graft. METHODS: To investigate the possibility of a pharmacodynamic interaction between ciprofloxacin and CsA, we conducted a case-control study in 42 patients who had received a kidney transplant and who were prescribed ciprofloxacin in the first 1-6 months after transplantation and in their matched controls (two per case) who did not receive ciprofloxacin during the study period. RESULTS: There was a twofold greater incidence (P=0.008) of ciprofloxacin use at 1-3 months (65%) than was observed at 4-7 months (35%) after transplantation. The proportion of cases experiencing at least one episode of biopsy-proven rejection 1-3 months posttransplant (45%) was significantly greater (P=0.004) than that of controls (19%). Furthermore, there was a marked increase (P<0.001) in the incidence of rejection temporally associated with ciprofloxacin use among cases (29%) compared with that experienced by the controls (2%). CONCLUSIONS: The possibility that ciprofloxacin increases rejection rates in renal transplant patients may be of clinical importance and therefore warrants further investigation.

Late acute rejection occurring in liver allograft recipients.

To study the effect of immunosuppressive reduction on the incidence and consequence of late acute rejection (LAR) in liver allograft recipients, mean daily prednisone dose, mean cyclosporine A (CsA) trough and nadir levels were retrospectively reviewed for the nearest 12-week period preceding six episodes of LAR in five liver allograft recipients (group 1). Results were compared with those from a cohort of 12 liver allograft recipients who did not develop LAR (group 2). LAR was defined as acute rejection occurring more than 365 days post-transplantation. Median follow-up for both groups was similar (504 days, range 367 to 1050, versus 511 days, range 365 to 666, not significant). Mean trough CsA levels were lower in patients with LAR compared with those without (224 +/- 66 ng/mL versus 233 +/- 49 ng/mL) but the difference was not statistically significant. In contrast, mean daily prednisone dose (2.5 +/- 1.6 mg/day versus 6.5 +/- 2.9 mg/day, P = 0.007) and CsA nadir values (129 +/- 60 ng/mL versus 186 +/- 40 ng/mL, P = 0.03) were significantly lower in patients who developed LAR compared with those who did not. Five of six episodes (83%) of LAR occurred in patients receiving less than 5 mg/day of prednisone, versus a single LAR episode in only one of 12 patients (8%) receiving prednisone 5 mg/day or more (P = 0.004). In all but one instance, LAR responded to pulse methylprednisolone without discernible affect on long term graft function. The authors conclude that liver allograft recipients remain vulnerable to acute rejection beyond the first post-transplant year; and reduction of immunosuppressive therapy, particularly prednisone, below a critical, albeit low dose, threshold increases the risk of LAR.

Aminoglycoside administration as a single daily dose. An improvement to current practice or a repeat of previous errors?

Despite the availability of newer and safer antibacterials, aminoglycosides continue to play a major role in the management of infections in hospitalised patients. The concept of single daily dose (SDD) regimens was introduced many years ago and is now receiving much attention as an alternative regimen for this class of drugs. To evaluate the rationale and clinical support for SDD schemes, we conducted a 'MEDLINE' search to locate relevant preclinical and clinical literature pertaining to this issue. The results of animal model and noncomparative clinical data tended to be variable and inconclusive. We were able to identify 28 prospective comparative clinical trials; however, only one was randomised, double-blind and of sufficient sample size to detect differences in efficacy between treatment arms, should any exist. Despite these flaws, our review suggests that SDD schemes appear to be no more efficacious and no less toxic, but may be less costly, than traditional multiple daily dose schemes. We also assessed the predicted disposition of tobramycin/gentamicin in 415 patients with known pharmacokinetic parameters. With doses of 7 mg/kg at intervals of between 24 and 60 hours (depending upon renal function), the maximum serum concentration at steady-state (Cmaxss) varied from 8.5 to 55.6 mg/L, while the Cminss was < 2.0 mg/L in the majority of patients. Mid-interval serum aminoglycoside concentrations were < 0.5 mg/L in up to 23% of patients, suggesting possible underdosage in certain patients with this scheme. More conclusive clinical evidence is necessary before SDD schemes should be adopted as standard clinical practice. Empirical weight-based dosage schemes appear to yield widely variable serum aminoglycoside concentrations which could be considered therapeutically inadequate or toxic.

Evaluation of a patient education program for solid organ transplant patients.

Medication counselling of transplant patients plays a major role in the outcome of the transplant. The medication counselling program at Vancouver Hospital and Health Sciences Centre for Solid Organ Transplant (SOT) patients consists of verbal counselling by a pharmacist, provision of medication teaching sheets, and patient participation in the self-medication program. The objectives of this study were to evaluate the effectiveness of the medication counselling program for SOT patients and to develop a series of tests to serve as a teaching tool. Solid organ transplant patients who were English speaking and tolerated oral medications were enrolled in the study. A prospective evaluation of the medication counselling program was done through a series of identical tests. Percent scores were calculated for each test, and pre-test scores (scores prior to counselling) were compared to post-test scores (scores after counselling). Twenty-eight SOT patients participated in the study. Patients scored an average of 25% on the pre-test prior to the counselling session and 66% on the post-test at the time of discharge. When scores on specific questions were compared, patients did well on drug identification, dosage and indications, but poorly on questions regarding side effects. Patient counselling improves medication knowledge in SOT patients as indicated by an increase in test scores. The combination of repeated counselling sessions and the participation in the self-medication program reinforces medication knowledge and maximizes retention of knowledge.

A prediction model for identifying alcohol withdrawal seizures.

A retrospective review of alcohol withdrawal seizures was performed at a private chemical-dependence treatment facility to help identify patients who were at high risk for having a seizure. Patients were identified by two means: controlled substance records were reviewed to determine patients having received intramuscular phenobarbital, and patient charts were reviewed for all patients with a discharge diagnosis of a seizure disorder. Two thousand and one patient records were reviewed; alcohol withdrawal seizure patients were identified. Twenty-eight randomly selected nonseizure patient records served as controls. The statistical test consisted of a discriminant function analysis. The data yielded a statistically significant predictive model for alcohol withdrawal seizures based on six interdependent patient variables which will be helpful in treating future patients undergoing alcohol withdrawal.