Systemic candidiasis in a surgical intensive care unit

Treatment for systemic candidiasis has often been withheld because of the nephrotoxicity of standard amphotericin B therapy, particularly in immunodepressed patients. The authors describe their experience between 1981 and 1983 with 29 such patients in the intensive care unit who were treated with low-dose amphotericin B. The diagnosis was made when endophthalmitis or persistent fungemia was present, or when Candida was cultured from three or more body sites. The daily dose of amphotericin B was 0.3 to 0.5 mg/kg. Treatment was accompanied by a mean increase in the serum creatinine value of 26% in patients who did not undergo dialysis before therapy, but this did not lead to renal failure. The overall death rate was 72.4%. Non-survival appeared to be associated with an inadequate total dosage (less than 6 mg/kg); survivors received a mean total dose of 570 mg. A retrospective analysis of positive peritoneal cultures failed to support their previously reported significance. The authors conclude that, in some instances, low-dose amphotericin B will effectively treat systemic candidiasis, resulting in little renal impairment, and that the criteria for such treatment require re-evaluation.     

Candida septic thrombosis of the great central veins associated with central catheters. Clinical features and management.

Candida septic thrombosis of the great central veins is rarely diagnosed during life, and reports of survival with this condition are exceedingly rare. Eight patients with Candida septic thrombosis of the central veins, with six survivors, are reported. Seven of eight patients had multiple organ system failure following surgery or trauma. All patients had received broad spectrum antibiotics and total parenteral nutrition via a central catheter. Every patient showed features of venous thrombosis with localizing extremity edema and high grade candidemia. Intensive amphotericin B therapy (mean daily dose: 0.7 mg/kg) in all patients, combined with 5-fluorocytosine in five cases, resulted in cure and long-term survival in six patients who received 1600 to 3435 mg (mean: 26 mg/kg) total dose. None of these patients developed renal failure, while four showed improving renal function during treatment. In contrast to Candida endocarditis, septic central vein thrombosis caused by Candida appears to be curable medically in the majority of cases with intensive amphotericin B therapy (total dose: greater than or equal to 22 mg/kg), combined when feasible with 5-fluorocytosine.     

Diagnosis and treatment of Candida vertebral osteomyelitis: clinical experience with a short course therapy of amphotericin B lipid complex

BACKGROUND: Musculoskeletal candidiasis occurs in some patients with candidemia resulting from organ infection, IV drug use, or indwelling central venous catheters. Diagnosis is often difficult because of vague symptomatology and a frequent afebrile course. CASE DESCRIPTION: Three patients with Candida vertebral osteomyelitis are presented. All followed the use of indwelling central venous access catheters and antimicrobial therapy between 6 months and 3 years earlier. In 2, fungemia with the same Candida spp. preceded the spondylodiskitis. These 3 patients bring to nearly 75 the number of reported individuals with what was once quite rare. Although IV amphotericin B doxycholate and fluconazole have usually been effective therapy over prolonged periods of time, we used liposomal amphotericin B to treat 2 of our 3 patients. Both received 5 mg/kg daily for 18-42 days that resulted in total disappearance of signs and symptoms. CONCLUSION: This relatively brief duration of therapy reduces treatment time and is cost-effective.     

Efficacy and safety of Amphotericin B Lipid Complex Injection (ABLC) in solid-organ transplant recipients with invasive fungal infections

Background: Fungal infections following solid-organ transplantation are a major source of morbidity and mortality. This report describes the efficacy and safety of Amphotericin B Lipid Complex Injection (ABLC) in solid-organ transplant recipients.
Methods: Three open-label, second-line treatment studies evaluated ABLC as a treatment for severe, life-threatening mycoses in patients who were refractory to or intolerant to conventional antifungal (mostly amphotericin B [AmB]) therapy or had pre-existing renal disease.
Results: The 79 solid-organ transplant recipients (25 heart, 20 liver, 17 kidney, 11 lung, 5 multiple, 1 pancreas) who received ABLC in these studies had the following fungal infections: aspergillosis (n=39); candidiasis (n=20); zygomycosis (n=8); cryptococcosis and histoplasmosis (n=3 each); and blastomycosis, cladosporiosis, fusariosis, Bipolaris hawaiiensis , Dactylaria gallopava , and an unspecified fungal infection (n=1 each). The median duration of ABLC therapy was 28 d (1–178 d). The daily dose ranged between 1.6 and 7.4 mg/kg (median, 4.6 mg/kg). The clinical response rate for the patients who could be assessed was 58% (39/67). Clinical response rates for heart, liver, kidney, and lung recipients were 59, 60, 67, and 40%, respectively; response rates for aspergillosis and candidiasis were 47 and 71%, respectively. Forty-six of the 79 patients (58%) survived for more than 28 d after the last dose of ABLC. Mean baseline serum creatinine was 3.2 mg/dL; 64 patients (81%) had stable (n=37) or improved (n=27) serum creatinine at the end of treatment.
Conclusions: ABLC is safe and effective treatment for fungal infections in solid-organ transplant recipients. Its renal-sparing properties are particularly suited for this high-risk population for renal failure.     

Cyclosporine Withdrawal Improves Renal Function in Heart Transplant Patients on Reduced-Dose Cyclosporine Therapy

Renal failure is a major cause of morbidity after heart transplantation. It is unclear whether calcineurin inhibitor (CNI) free immunosuppression provides more nephroprotection than low-dose CNI therapy. Thirty-nine patients with renal failure on low-dose cyclosporine A (CsA) were studied (62.9 +/- 8.7 years, five female, 8.2 +/- 4.3 years posttransplant, serum creatinine: 1.9 +/- 0.3 mg/dL, calculated GFR (cGFR): 48.2 +/- 18.3 mL/min, CsA C0 level: 64.0 +/- 19.9 ng/mL). All patients had been treated with low-dose CsA >6 months, renal function was stable or slowly decreasing (creatinine 1.7-3.5 mg/dL). Nineteen patients were randomized to discontinuation of CsA and overlapping rapamycin therapy initiation (RAPA), 20 patients continued low-dose CsA (control). Three patients (16%) discontinued rapamycin medication for side effects (diarrhea, skin rash), two patients developed pneumonia and pulmonary embolism, respectively, no rejection or other infectious complications were seen. After 6 months, renal function in the control group was unchanged. In the RAPA group, renal function markedly improved (creatinine: 2.08 +/- 0.15 to 1.67 +/- 0.13 mg/dL, cGFR: 48.5 +/- 21.4 to 61.7 +/- 21.4 mL/min (p < 0.001 within and between groups)). In carefully selected late survivors following heart transplantation who are at low risk of rejection, CNI-free rapamycin-based immunosuppression improves cGFR even in those already receiving low-dose CsA therapy. The results of this study warrant further confirmation in larger clinical trials that are powered to assess clinical outcomes.     

Correlates of acute renal failure in patients receiving parenteral amphotericin B

BACKGROUND: While parenteral amphotericin B is an effective therapy for serious fungal infections, it frequently causes acute renal failure (ARF). This study identified correlates of ARF in amphotericin B therapy and used them to develop clinical prediction rules. METHODS: All 643 inpatients receiving parenteral amphotericin B therapy at one tertiary care hospital were included. Data regarding correlates were obtained both electronically and from manual chart review in a subsample of 231 patients. ARF was defined as a 50% increase in the baseline creatinine with a peak > or =2.0 mg/dL. RESULTS: Among 643 episodes, ARF developed in 175 (27%). In the larger group, the only independent correlate of ARF was male gender (OR = 2.2, 95% CI, 1.5 to 3.3). In the subsample (N = 231), independent correlates of ARF were maximum daily amphotericin dosage, location at the time of initiation of amphotericin therapy, and concomitant use of cyclosporine. These data were used to develop two clinical prediction rules. A rule using only data available at initiation of therapy stratified patients into groups with probability of ARF ranging from 15 to 54%, while a rule including data available during therapy (maximum daily dose) stratified patients into groups with probability of ARF ranging from 4 to 80%. CONCLUSIONS: Acute renal failure occurred in a quarter of the patients. Correlates of ARF at the beginning and during the course of amphotericin therapy were identified and then combined to allow stratification according to ARF risk. These data also provide evidence for guidelines for the selection of patients for alternative therapies.     

Analysis of factors affecting the course of renal disease progression in patients with established renal insufficiency

All renal diseases ultimately progress to end-stage renal disease after renal dysfunction develops except for acute renal failure or rapidly progressive glomerulonephritis. However, renal function can be preserved for long periods in patients with mild renal insufficiency. We examined the factors affecting the progression of renal disease in patients with established renal insufficiency. We enrolled 38 patients with renal insufficiency diagnosed at the first visit and who were followed up for at least 3 years. We retrospectively recorded all information relating to serum creatinine and blood pressure levels during the follow-up periods. The patients were categorized as group A(n = 11), long-term renal survivors(at least 8 years), group B(n = 22), short-term renal survivors(3 to 8 years) and others(n = 5). Basal renal diseases were variable, and included IgA nephropathy, membranous nephropathy, focal segmental glomerulosclerosis, hypertensive glomerulosclerosis, tubulo-interstitial disease and lupus nephritis. Except for the degree of urinary occult blood, no other clinical data obtained at the first visit differed between groups A and B. Overall blood pressure levels throughout the entire clinical course also did not differ between the two groups. However, mean blood pressure levels before serum creatinine had reached the level of 2.0 mg/dl were significantly lower in group A compared with group B (96 +/- 7.8 vs. 103 +/- 6.3 mmHg, p < 0.05). We considered that the serum creatinine level of the so-called "point of no return" might be 2.0 mg/dl. In conclusion, blood pressure should be strictly controlled before serum creatinine levels reach 2.0 mg/dl.     

Candida pyelonephritis complicated by fungaemia in obstructive uropathy

Fungal pyelonephritis caused by Candida species and Torulopsis without evidence of systemic organ involvement is uncommon. Most reported cases have been in diabetic females or in patients on immunosuppressive drugs. We report 3 cases of elderly men who had fungal pyelonephritis presumed secondary to obstructive uropathy. All subsequently developed fungaemia. Two were managed successfully with percutaneous or ureteric stents and systemic antifungal therapy; the third died despite systemic amphotericin B.     

A new ancient irrigation therapy for childhood renal candidiasis

Methylene blue (MB) alone, MB metabolites in the urine and the effect of MB plus alkalization on Candida species were determined. MB was used for the treatment of childhood renal candidiasis (CRC) in 3 patients as an irrigating solution. Besides irrigation, fluconazole 3 mg/kg/day intravenously and MB 0.2 mg/kg/day were administered perorally. Urine cultures were cleared of Candida. DMSA scans obtained after 6 months showed no evidence of scarring. MB can be used for irrigation of the urinary tract, with fewer side effects than amphotericin B (AB). Additionally we advocate the use of ureteral catheters instead of nephrostomy in the treatment of CRC.     

Renal effects of amphotericin B lipid complex

A study was conducted to compare the renal effects of amphotericin B lipid complex (ABLC), a lipid formulation of the widely used antifungal medication, with conventional amphotericin B (AmB) in the treatment of serious fungal infections, including invasive candidiasis, cryptococcal meningitis, and aspergillosis. The clinical experience of ABLC includes two types of open-label studies: randomized comparative (ABLC 5 mg/kg/d compared with AmB 0.6 to 1 mg/kg) and emergency use. In the comparative studies, changes in serum creatinine were evaluated three ways: doubling of the baseline value, an increase from < or = 1.5 mg/dL at baseline to > or = 1.5 mg/dL, and an increase from < or = 1.5 mg/dL at baseline to > or = 2.0 mg/dL. More patients in the AmB group reached these end points than in the ABLC group (P < or = 0.007), and the time needed to reach each of these end points was significantly shorter for the AmB group (P < or = 0.02). Increased serum creatinine was reported as an adverse event more frequently by patients receiving AmB than by patients receiving ABLC. In the emergency use study, a steady and statistically significant decrease in serum creatinine was observed among patients who started ABLC treatment with serum creatinine greater than 2.5 mg/dL due to prior AmB treatment. ABLC offers the physician a valuable, less-nephrotoxic alternative to AmB for the treatment of patients with severe, invasive fungal infections.     

A randomized prospective trial of amphotericin B lipid emulsion versus dextrose colloidal solution in critically ill patients.

BACKGROUND: Amphotericin B is the agent of choice for most invasive fungal infections in critically ill patients. It is associated with at least a 50% incidence of nephrotoxicity, despite prophylactic measures such as sodium loading. Newer formulations of amphotericin B are available but are costly and have unknown bioavailability in critically ill patients. Previous trials in neutropenic and critically ill patients have demonstrated that mixing amphotericin B with 20% lipid solution (Intralipid; Clintec Nutrition, Deerfield, III) may decrease nephrotoxicity. METHODS: In this randomized, prospective clinical trial, patients with positive fungal blood cultures, tracheal/sputum cultures or peritoneal cavity cultures were randomized to receive either 0.5 mg/kg per day of amphotericin B dextrose or 1.0 mg/kg per day of amphotericin B lipid emulsion. Duration of therapy was determined by the primary care team. Weekly 24-hour creatinine clearance was measured until 2 weeks after amphotericin B therapy was completed. RESULTS: The two groups were similar based on age, white blood cell count, serum creatinine, and creatinine clearance at the beginning of therapy. The group receiving amphotericin B lipid emulsion had significantly less decrease in creatinine clearance compared with controls, despite receiving significantly more amphotericin B. CONCLUSION: Amphotericin B lipid emulsion can be given at a higher total cumulative dose than amphotericin B dextrose with less nephrotoxicity.     

Clinical efficacy of flucytosine on urinary candidiasis

An antifungal agent (Flucytosine) was used to treat urinary candidiasis in 9 patients who had an indwelling catheter and developed fungal colony counts greater than 10(4). Among 9 patients with catheter drainage, urologic underlying diseases were benign prostatic hyperplasia in 7 and a neurogenic bladder in one patient all of whom had accompanied diabetes mellitus. Only one patient was supravesically diverted from the upper urinary tract through an indwelling catheter of bilateral ureterocutaneostomy after the removal of a tumorous bladder. All patients had previously received antimicrobials. Isolated strains of Candida were Candida albicans in 6, Candida tropicalis in 2, and Candida parapsilosis in one patient. Out of 9 patients having received daily administration of 1,500 mg Flucytosine for 2 weeks, 7 patients subsequently had no yield of fungal colony after the treatment. Minimum inhibitory concentration (MIC) of this agent was determined at the range of 0.1 to 0.2 microgram/ml in 5 patients with C. albicans and 0.2 microgram/ml in both patients with C. tropicalis. Otherwise, a high MIC of over 100 micrograms/ml indicating resistance to this agent was observed in only 2 patients with C. albicans and C. parapsilosis. Three of the 7 patients had recurrent urinary Candida infection even 2 weeks after the discontinuation of this antifungal therapy despite rapid and excellent eradication of urinary candidiasis. From these results, Flucytosine may be one of the most promising antifungal agent with a low MIC in the treatment of compromised urinary Candida infection and should be occasionally supplemented with a topical instillation of amphotericin B without any serious complication in the prevention of recurrence.     

The role of percutaneous nephrostomy in the management of obstructing candidiasis of the urinary tract in infants

We report on 5 neonates with obstructive urinary tract candidiasis in whom percutaneous nephrostomy had a major role in management. The advantages of percutaneous nephrostomy in this setting include prompt drainage of the obstructed renal pelvis or ureter, direct access to obtain specimens from the renal pelvis to confirm the diagnosis, direct irrigation of the fungus balls with amphotericin B and an access route for fragmentation of fungus balls by guide wire manipulation. In 3 cases percutaneous placement of the nephrostomy tube was successful in obtaining and maintaining access to the renal pelvis, while in 2 surgical intervention was required because of problems maintaining placement of the percutaneous catheters. Percutaneous nephrostomy with antegrade amphotericin B irrigation, coupled with systemic antifungal therapy, is the mainstay of treatment. The usefulness of ultrasonography in the early diagnosis of renal candidiasis also is emphasized.     

Treatment of candidosis in severely injured adults with short-course, low-dose amphotericin B

Thirty-three (0.7%) of 4,818 trauma patients admitted between January 1, 1987, and July 1, 1989, developed invasive candidosis requiring IV antifungal therapy. All patients were seriously traumatized. Before developing candidosis, all patients had documented bacterial infections. These infections were generally polymicrobial and were treated with multiple broad-spectrum antibiotics (an average of 5.4 antibiotics for 17.2 days). Twenty-eight (85%) of 33 patients received enteral feedings for an average of 11 days +/- 1.5 (SEM) before developing candidosis and 24 (73%) received NG/oral nystatin for an average of 7.6 days +/- 0.9 before developing candidosis. All patients with candidosis were treated with intravenous amphotericin B: cumulative dose of 157.3 mg +/- 31.3 mg given over 10 days +/- 1.1. One patient developed recurrent candidosis despite NG/oral prophylaxis and enteral feedings. Six patients (18%) died due to sepsis and multiple organ failure. The patients who died did not objectively differ from the survivors. Candidosis is an infrequent infection in severely injured patients. Candidosis was invariably preceded by treatment with multiple broad-spectrum antibiotics for a variety of polymicrobial bacterial infections. NG/oral nystatin and enteral feedings did not prevent candidosis, in contrast to widely accepted beliefs. Amphotericin B therapy was safe. Recurrent candidosis was unusual. Candida infections had a high mortality rate associated with multiple blood transfusions and prolonged hospitalization. Candidosis represents a sign of severe injury and illness but can be amenable to prompt, aggressive treatment.     

Rapid diagnosis of Candida sepsis in surgical patients

Systemic candidiasis, an increasingly common disease, is associated with an extremely high mortality. Because of toxicity associated with amphotericin B therapy, clinicians are reluctant to initiate therapy until the presence of candidiasis is conclusively demonstrated. Using culture methods, such proof may not be forthcoming or may be available only late in the course of the disease. During the last 17 months, a new antigen latex agglutination test for candidiasis has been evaluated. Results indicate that this new test allows early, accurate diagnosis of the disease. In 36 consecutive cases of culture-proven candidiasis in surgical patients, the test was found to be 94.4 per cent sensitive and 100 per cent specific. On the basis of these findings initiation of amphotericin B therapy in patients with a positive Candida antigen titer is recommended.     

Abdominal aortic aneurysm repair in patients with preoperative renal failure

The purpose of this study was to determine the effect of preoperative renal failure on the outcome of patients undergoing infrarenal abdominal aortic aneurysm (AAA) repair. Of 251 patients undergoing AAA repair from 1977 to 1984, 10% had evidence of preoperative chronic renal failure. These patients were classified according to their preoperative serum creatinine values; group I had preoperative creatinine levels of 2 to 4 mg/dl, group II had creatinine levels greater than 4 mg/dl but no history of hemodialysis, and group III consisted of patients on chronic hemodialysis before operation. One of 16 patients in group I developed transient high-output renal failure postoperatively. Four of the six patients in group II (67%) developed significant postoperative deterioration of renal function and required acute hemodialysis. Of the four patients in group III maintained on chronic hemodialysis preoperatively, one died of sepsis from an ischemic colon. This experience suggests that patients with mild renal dysfunction (serum creatine value less than 4 mg/dl) can undergo elective AAA repair without additional morbidity. Patients on hemodialysis before operation can also safely undergo surgical repair of their AAAs electively if dialyzed the day before operation. Patients with severe renal dysfunction (serum creatinine greater than 4 mg/dl) who are not on hemodialysis should be considered for dialysis preoperatively in an attempt to reduce the high incidence of serious postoperative renal functional deterioration and subsequent morbidity.     

Successful use of kidneys from deceased donors with acute renal failure

BACKGROUND: Kidneys from deceased donors with acute renal failure are not widely used. OBJECTIVE: To compare outcomes for recipients of kidneys from donors with acute renal failure at organ recovery with outcomes for recipients of kidneys from donors with normal serum levels of creatinine. METHODS: Records of deceased donors and recipients of their organs at the Saudi Center for Organ Transplantation from 2003 to 2005 were reviewed. A total of 33 donors (donating 65 kidneys to 65 recipients) with elevated serum levels of creatinine (>1.7 mg/dL) and 94 donors (donating 188 kidneys to 188 recipients) with normal (<1.1 mg/dL) serum levels of creatinine at organ recovery and their respective recipients were compared. Both groups had normal creatinine levels at admission. RESULTS: Recipients in both groups had similar renal function at discharge and follow-up. Delayed graft function occurred more often (P= .009) in the recipients of kidneys from donors with acute renal failure (47.7%) than in recipients of kidneys from donors with normal creatinine levels (29.8%). Elevation of serum level of creatinine at organ recovery did not correlate significantly with kidney function at discharge or last follow-up or with graft survival. CONCLUSIONS: Survival of patients or grafts at 1, 2, and 3 years did not differ significantly between the recipients in the 2 groups. Only the frequency of delayed graft function differed between the 2 groups.     

Prediction of mortality in patients with bacteremia: the importance of pre-existing renal insufficiency

Pre-existing renal insufficiency serves as a common risk factor in the development of acute renal failure. Acute renal failure is a common finding in patients with bacteremia and is associated with poor prognosis. A total of 2722 consecutive patients 18 years old or older, fulfilling strike criteria of bacteremia or fungemia were prospectively evaluated to establish the prognostic importance of pre-existing renal insufficiency in bacteremic patients. They were classified according to serum creatinine levels upon admission into three groups. 915 patients had normal creatinine levels (< or = 1.0 mg/dL), 1528 had mild to moderate renal failure (creatinine 1.1-3 mg/dL) and 279 patients had severe renal failure upon admission (creatinine > 3.0 mg/dL). Mild to severe renal failure upon admission was associated with old age, male gender, diabetes mellitus, ischemic heat disease, hypertension and congestive heart failure. The serum albumin in patients with severe renal failure was significantly low, with a mean of 2-9 mg/dL. Urinary tract infections were more prevalent in patients with mild to severe renal failure, while intravenous line infections, bacterial endocarditis and soft and skin tissue infections were more common in patients with normal renal function. In the 279 patients with severe renal failure the mortality rate was significantly higher (50%) compared to patents with mild to moderate renal failure and patients with normal renal function (21% and 26% respectively, p = 0.0001). Multiple regression analysis revealed that pre-existing serum creatinine > 3 mg/dL was significantly associated with death attributable to bacteremia (OR = 1.7, 95% CI 1.0-2.7). In conclusion, adult bacteremic patients with pre-existing serum creatinine above 3 mg/dL upon admission are at increased risk of mortality due to bacteremia than patients with normal or mild to moderate renal failure.     

Candida infection in the severely burned patient--a successful treatment concept with liposomal amphotericin B]

Candida sepsis is a very serious complication in severely burned patients. This mainly affects patients whose immune system is weakened by illness and/or by drugs. Often diagnosis is difficult because candida sepsis occurs after an initial infection, but therapy is always difficult. Good fungicidal drugs are available, but their side effects limit their effectivity. Two severely burned patients who were suffering from a gram-negative sepsis confirmed by clinical and laboratory data developed candida sepsis. Conventional therapy failed, and both patients suffered from renal failure with constantly high candida-latex-antigen titre. By means of the liposomal encapsulated amphotericin B, which has the same fungicidal effect as amphotericin B, but without its limiting side effects, both, patients could be saved. The kidneys functioned as normal again, the laboratory findings were normal when the patients were discharged.     

Pharmacokinetics of sirolimus in heart transplant recipients with chronic renal impairment

BACKGROUND: A common clinical problem following organ transplantation is the development of renal failure due to calcineurin inhibitors. Sirolimus offers the potential of providing appropriate immunosuppression without nephrotoxicity. This study evaluates the impact of sirolimus monotherapy on renal function in patients late following heart transplantation and correlates trough sirolimus levels with area-under-the-concentration time curve measurements. METHODS: Six male patients with renal impairment late following heart transplantation (mean 8 years) were offered sirolimus therapy. Calcineurin inhibition was discontinued in all patients on commencing sirolimus. Patients started on sirolimus 2 to 5 mg/d orally. Venous blood samples for pharmacokinetic studies and repeat creatinine clearance were performed before and 6 weeks after commencement of sirolimus in all subjects. RESULTS: Sirolimus trough levels accurately reflected sirolimus area-under-the-concentration time curve measurements. There was no change in renal function. Mean creatinine clearance prior to commencing sirolimus was 26.7 (12.2) mL/min and the post-sirolimus creatinine clearance performed 6 weeks later was 23.4 (11.7) mL/min (P = .64). CONCLUSIONS: Trough levels of sirolimus correlate with drug exposure and may be used to monitor sirolimus therapy. No improvement in renal function following calcineurin inhibitor withdrawal occurred in this cohort.