Chronic amphotericin B nephrotoxicity in the rat: protective effect of calcium channel blockade

Amphotericin B is used despite predictable nephrotoxicity because it remains the most efficacious agent currently available for systemic fungal infections. It has been previously shown that calcium channel blockade prevents renal vasoconstriction and blunts the fall in glomerular filtration rate during acute amphotericin B infusion in the rat. Therefore, the effect of cotreatment with diltiazem on nephrotoxicity during chronic daily amphotericin therapy in rats was studied. Rats were given diltiazem (45 mg/kg, 1 h before and 1 h after amphotericin) or vehicle by gastric tube; and amphotericin B (5 mg/kg/day i.p.) for 10 days. Control rats received corresponding vehicles by gastric tube and daily i.p. infection. Renal function was determined 24 h after the last dose of amphotericin or vehicle. Serum creatinine rose significantly in rats receiving amphotericin alone (initial versus final, 0.50 +/- 0.07 versus 1.09 +/- 0.20 mg/dL; P less than 0.05) but not with amphotericin plus diltiazem (0.54 +/- 0.11 versus 0.84 +/- 0.23 mg/dL; P was not significant). Amphotericin rats had a marked decrease in glomerular filtration rate (amphotericin versus control, 0.28 +/- 0.04 versus 1.23 +/- 0.08 mL/min/g kidney wt; P less than 0.05) and renal plasma flow (1.63 +/- 0.19 versus 3.50 +/- 0.40 mL/min/g kidney wt; P less than 0.05). These adverse renal hemodynamic effects were prevented by cotreatment with diltiazem (amphotericin plus diltiazem; glomerular filtration rate, 0.82 +/- 0.18 mL/min/g kidney wt; P less than 0.05 versus amphotericin; P was not significant versus control; renal plasma flow, 3.24 +/- 0.63 mL/min/g kidney wt; P less than 0.05 versus amphotericin; P was not significant versus control).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of salt supplementation on amphotericin B nephrotoxicity

It has been suggested that salt loading protects against amphotericin B-induced nephrotoxicity. The influence of saline loading on the nephrotoxic response to amphotericin B (50 mg/dose given i.v. over 4 hr 3 X/week for 10 weeks) was assessed in two groups of ten patients each who were diagnosed with mucocutaneous leishmaniasis. Patients were randomized to receive either 1 liter of 0.9% saline or 1 liter of 5% dextrose in water, administered i.v. over one hour in a double-blinded manner, directly prior to amphotericin B administration. Renal function was monitored on a weekly basis two days after the last dose of amphotericin B. Baseline characteristics were similar in both groups except for a slightly higher serum creatinine concentration (Cr) in the saline group (0.8 +/- 0.05 vs. 0.6 +/- 0.04 mg/dl). Baseline sodium (Na) excretion was relatively high (262 +/- 23 mmol/day in the dextrose group and 224 +/- 17 mmol/day in the saline group). None of the patients sustained an increase in Cr to values greater than 1.7 mg/dl. Although mean Cr remained within normal, there was a significant difference between the two groups over the ten week period, with the dextrose group sustaining a significant increase in Cr and the saline group remaining unchanged. Serum potassium (K) levels fell in both groups necessitating oral K supplementation. The saline group required significantly greater amounts of K supplementation to maintain a normal serum K. Amphotericin B caused a rapid reduction in the acidification ability of the kidney in response to an ammonium chloride load. Under these conditions, the saline group had a poorer ability to acidify the urine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Candida infections in surgical patients. Dose requirements and toxicity of amphotericin B

The natural history of candidiasis in general surgical patients has been poorly documented, and the toxicity of amphotericin B is widely heralded. For these reasons therapy for candidiasis is frequently withheld in situations where antimicrobial treatment seems indicated on clinical grounds. The clinical courses of 47 general surgical patients who received amphotericin therapy for presumed Candida infection were reviewed. Nineteen patients had had solid tumors, but 12 were either localized or resected tumors. Only nine patients had received prior cancer themotherapy. Twenty-one patients were treated for fungemic disease, 10 for Candida in peritonitis fluid, and 16 for apparent colonization associated with fever and organ failure syndromes. Pre-existing renal or other organ failure was the primary determinant of survival with 4/22 survivors (18%) in patients with renal failure compared with 17/25 (78%) survivors in patients without such organ failure. In patients with serum creatinine values less than 2.5 mg/dl, amphotericin therapy was associated with a transient 30% fall in creatinine clearance and a proportionate rise in serum creatinine. Dose response curves were determined and revealed substantial sterilization of cultures in both fungemic and nonfungemic patients receiving greater than or equal to 6 mg/kg. This was confirmed by autopsy material. We suggest that in this acutely ill patient popoulation uncontrolled infection is the primary determinant of organ failure. Short-term limited dosing with amphotericin B (6-8 mg/kg total dose) in conjunction with appraisal of clinical response is adequate therapy for most presumed Candida infections. Long-term high dose therapy, such as that recommended in immuodepressed patients, is not a routine necessity.     

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.     

Targeted Prophylaxis With Amphotericin B Lipid Complex in Liver Transplantation

The purpose of this study is to prospectively evaluate a strategy in which prophylaxis with amphotericin B lipid complex at 3 different dosages was targeted to liver transplant recipients at high risk for the development of invasive fungal infection (IFI). High risk was defined as a postoperative requirement for prolonged (≥5 days) intensive care unit (ICU) treatment. Consecutive high-risk patients were administered prophylaxis with amphotericin B lipid complex from day 5 after orthotopic liver transplantation (OLT) until ICU discharge or death. The first 10 eligible patients were administered 5 mg/kg/d, the next 10 patients were administered 2.5 mg/kg/d, and a final 10 patients were administered 1 mg/kg/d. Drug safety and efficacy were assessed before each dosage reduction. During the study period, 130 adult patients underwent 137 OLTs. Thirty patients fulfilled the entry criteria and were administered prophylaxis with amphotericin B lipid complex. No patient developed proven IFI during prophylaxis. Cultures from normally sterile sites (blood and abdominal drain fluid) always showed negative results. All fungal isolates were sensitive in vitro to amphotericin B. There was no significant difference in colonization scores among the groups of patients administered different dosages of amphotericin B lipid complex. No death, serious adverse reaction, or nephrotoxicity was attributed to amphotericin B lipid complex. We conclude that prophylaxis with amphotericin B lipid complex targeted to patients requiring prolonged ICU treatment after OLT appears to be well tolerated and may prevent IFI. Our current policy is to use amphotericin B lipid complex, 1 mg/kg/d, as antifungal prophylaxis in this high-risk group. (Liver Transpl 2000;6:588-595.)     

Amphotericin selectively increases peritoneal ultrafiltration

Because amphotericin B is known to affect transport rates across biologic membranes, the effects of this agent on transport parameters in an animal model of peritoneal dialysis were investigated. When amphotericin B in doses ranging from 0.5 to 25 mg/kg was instilled intraperitoneally with commercial dialysis solution, diffusive clearances of phosphate and urea did not differ from control values measured in the same animals, and only a modest increase in potassium clearance was detected. Ultrafiltration due to the osmotic gradient induced by the dextrose content of the dialysis solution increased significantly to 0.31 mL/kg/min with amphotericin B, compared with control values of 0.18 mL/kg/min. The drug did not affect dextrose transport and the osmotic gradient did not differ in the two groups. Hence, the ultrafiltration coefficient was higher with amphotericin B (14 microL/kg/min/mosm), than during control dialyses (6 microL/kg/min/mosm). Increased water flux was detected at the lowest dose and there was no dose relationship over the range studied. Amphotericin B may be the type of agent that will be clinically useful in patients with reduced peritoneal ultrafiltration capacity, and safer analogues should be explored.     

Influence of sodium intake on Amphotericin B-induced nephrotoxicity among extremely premature infants

Amphotericin B (AmphoB) remains the preferred therapy for invasive fungal infections despite many side effects, such as nephrotoxicity and electrolyte imbalance. Our previous study suggested that high sodium (Na) intake >4 mEq/kg per day may be associated with lower nephrotoxicity in extremely premature infants treated with AmphoB. Subsequently, it became a standard of care in our unit to administer Na >4 mEq/kg per day to extremely premature infants treated with AmphoB. The purpose of this study was to evaluate the effect of high Na intake > 4 mEq/kg per day on the incidence of AmphoB-induced nephrotoxicity among extremely premature infants with birth weight <1250 gm. All extremely premature infants with birth weight <1250 gm born between 1992 and 2004 and treated with AmphoB for systemic fungal infections were included in the study. The study infants were divided into two groups: a control (CL) group (1/1992–12/1999, n = 21) consisting of extremely premature infants given a maintenance Na intake during AmphoB therapy, and a high sodium intake (High Na) group (1/2000–12/2004, n = 16) consisting of extremely premature infants given a high Na intake >4 mEq/kg per day during AmphoB therapy. Nephrotoxicity was defined as serum creatinine levels >1 mg/dl, urinary output (UOP) < 1 ml/kg per hour or a decrease in UOP of 50%, compared with the previous 2 days, and persisting for at least 2 days. Invasive fungal infection was diagnosed in 5.7% of the infants (44/763 infants). Thirty-seven infants were eligible for the study and seven were excluded. There were no differences between the two groups in gestational age, birth weight, age at fungal infection diagnosis, length of AmphoB therapy, daily fluid intake or hyponatremia. Nephrotoxicity was significantly higher in the CL group than in the High Na group (13/21 vs. 3/16; P = 0.02). In the CL group, nephrotoxicity occurred at (mean ± SD) 1.9 ± 3.2 days after the initiation of AmphoB treatment and lasted for 5.5 ± 4.7 days. In this group, nephrotoxicity occurred in two of the 13 infants before the initiation of AmphoB therapy. In the High Na group, nephrotoxicity occurred before the start of AmphoB therapy in two of the three infants. In the third infant, nephrotoxicity lasted for 1 day. Mean Na intake was not different between the two groups during the 4-day period prior to AmphoB therapy. Mean Na intake during the first 10-day period of AmphoB therapy was significantly lower in the CL group (3.7 vs 6.2; P < 0.001). Conclusion: High Na intake was associated with a reduction in the incidence of AmphoB-induced nephrotoxicity in extremely premature infants with birth weight <1250 gm. We recommend the use of a high Na intake of >4 mEq/kg per day for extremely premature infants during Amphotericin B therapy. This work was presented in part at the 2006 Pediatric Academic Societies Meeting, April 29–May 2, 2006, San Francisco, California.     

Double-blind placebo-controlled trial of fluconazole to prevent candidal infections in critically ill surgical patients

OBJECTIVE: To evaluate the prophylactic use of enteral fluconazole to prevent invasive candidal infections in critically ill surgical patients. SUMMARY BACKGROUND DATA: Invasive fungal infections are increasingly common in the critically ill, especially in surgical patients. Although fungal prophylaxis has been proven effective in certain high-risk patients such as bone marrow transplant patients, few studies have focused on surgical patients and prevention of fungal infection. METHODS: The authors conducted a prospective, randomized, placebo-controlled trial in a single-center, tertiary care surgical intensive care unit (ICU). A total of 260 critically ill surgical patients with a length of ICU stay of at least 3 days were randomly assigned to receive either enteral fluconazole 400 mg or placebo per day during their stay in the surgical ICU at Johns Hopkins Hospital. RESULTS: The primary end point was the time to occurrence of fungal infection during the surgical ICU stay, with planned secondary analysis of patients "on-therapy" and alternate definitions of fungal infections. In a time-to-event analysis, the risk of candidal infection in patients receiving fluconazole was significantly less than the risk in patients receiving placebo. After adjusting for potentially confounding effects of the Acute Physiology and Chronic Health Evaluation (APACHE) III score, days to first dose, and fungal colonization at enrollment, the risk of fungal infection was reduced by 55% in the fluconazole group. No difference in death rate was observed between patients receiving fluconazole and those receiving placebo. CONCLUSIONS: Enteral fluconazole safely and effectively decreased the incidence of fungal infections in high-risk, critically ill surgical patients.     

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.     

Contrasting effects of amphotericin B and the solvent sodium desoxycholate on peritoneal transport

To distinguish amphotericin B effects on peritoneal transport from those of the solvent, sodium desoxycholate, dialyses in intact rabbits with either substance added intraperitoneally were compared to controls. Powered amphotericin B added to instilled dialysis fluid increased peritoneal ultrafiltration from 0.31 to 0.44 ml/kg/min (p less than 0.02), but did not affect mass transport (e.g. urea clearance changed from 0.86 to 1.04 ml/kg/min). In contrast, 10 mg of desoxycholate induced peritoneal irritation and raised clearances of urea (0.76-1.34 ml/kg/min), potassium, phosphate and dextrose, but did not affect ultrafiltration. Intraperitoneally, 1 mg/kg of desoxycholate changed clearances inconsistently, but lowered the ultrafiltration rate from 0.33 to 0.21 ml/kg/min. The dialysate-plasma dextrose gradient dissipated faster with 10 mg/kg of desoxycholate. Amphotericin B tended to raise ultrafiltration per osmotic gradient and mass transport of sodium. Selective increase in fluid flux results from amphotericin B, not its solvent.     

Abdominal candidiasis in surgical patients

Although abdominal candidiasis in critically ill surgical patients is becoming increasingly common, optimal management has not been defined. We treated 16 patients with abdominal candidiasis over a 36 month period. Violation of the gastrointestinal tract mucosa was the most common precipitating event (13 patients). Predisposing factors included: CVP catheters, broad spectrum antibiotics, and parenteral hyperalimentation in all patients, H2-blockers/antacids in 14 patients, as well as malnutrition (7 patients), DM (3 patients), alcoholism (3 patients), and steroids/chemotherapy (3 patients). Candida was isolated from an abscess in seven patients, peritoneal fluid in six patients and both in three patients. In four patients abdominal candidiasis was preceded by positive cultures from blood or two peripheral sites which had not been treated. All patients were treated with amphotericin B (146-4000 mg) without any major adverse effects. Fungal infection was eradicated in ten patients; three patients succumbed to candidiasis. Patients treated within seven days required less Amphotericin B and appeared to have a better outcome than those having delayed treatment. The authors conclude that abdominal candidiasis is a potentially lethal infection in critically ill surgical patients that should be aggressively treated. Amphotericin B can be safely administered and concurrent antibiotics need not be stopped.     

Comparative safety of amphotericin B lipid complex and amphotericin B deoxycholate as aerosolized antifungal prophylaxis in lung-transplant recipients

BACKGROUND: Aerosolized administrations of amphotericin B deoxycholate (AmBd) and amphotericin B lipid complex (ABLC) in lung transplant recipients were compared for safety and tolerability. The incidence of invasive fungal infections in patients receiving aerosolized amphotericin B formulations as sole prophylaxis was determined. METHODS: A prospective, randomized (1:1), double-blinded trial was conducted with 100 subjects. AmBd and ABLC were administered postoperatively by nebulizer at doses of 25 mg and 50 mg, respectively, which were doubled in mechanically ventilated patients. The planned treatment was once every day for 4 days, then once per week for 7 weeks. Treatment-related adverse events and invasive fungal infections were quantitated for 2 months after study drug initiation. RESULTS: Intent-to-treat analysis revealed study drug was discontinued for intolerance in 6 of 49 (12.2%) and 3 of 51 (5.9%) patients in the AmBd- and ABLC-treated groups, respectively (p=0.313). Subjects receiving AmBd were more likely to have experienced an adverse event (odds ratio 2.16, 95% confidence interval 1.10, 4.24, p=0.02). Primary prophylaxis failure within 2 months of study drug initiation was observed in 7 of 49 (14.3%) AmBd-treated patients and 6 of 51 (11.8%) ABLC-treated patients. No fungal pneumonias were observed. Only two (2%) patients experienced documented primary prophylaxis failure with Aspergillus infections within the follow-up period. CONCLUSIONS: Both aerosol AmBd and ABLC appear to be associated with a low rate of invasive pulmonary fungal infection in the early posttransplant period. Patients receiving ABLC were less likely to experience a treatment-related adverse event.     

Effects of H2-receptor antagonists on renal function in cyclosporine-treated renal transplant patients

H2-receptor antagonists have been frequently avoided in cyclosporine-treated transplant patients because of concern regarding possible exacerbation of nephrotoxicity. To determine whether the reported increase of serum creatinine levels in cyclosporine-treated transplant patients receiving H2-receptor antagonists was due to a true decrease in glomerular filtration rate or was secondary to altered renal tubular handling of creatinine, simultaneous inulin and creatinine clearances were analyzed in 11 cyclosporine-treated renal transplant recipients before and after H2-receptor antagonist administration. Seven patients received one week of cimetidine 300 mg p.o. four times daily and eight received one week of ranitidine 150 mg p.o. two times daily. Prior to study, all patients had stable renal function and were maintained on prednisone (mean dose 0.2 +/- 0.01 mg/kg/day) and cyclosporine (mean dose 5 +/- 0.6 mg/kg/day). Four patients were also receiving azathioprine (2 mg/kg/day). Cimetidine administration resulted in a significant increase (P less than 0.05) in mean serum creatinine concentration from 2.0 +/- 0.3 mg/dl to 2.4 +/- 0.3 mg/dl and a significant reduction (P less than 0.05) in mean creatinine clearance remained unchanged during this same period. Serum creatinine levels returned to baseline values for all patients following discontinuation of the drug. Ranitidine administration had no consistent effect on serum creatinine concentration, creatinine clearance or inulin clearance. Cyclosporine trough levels and BUN were unchanged by either drug. These results confirm previous observations demonstrating an increase in serum creatinine and a reduction in creatinine clearance following administration of H2 receptor antagonists, especially cimetidine. Failure to document a simultaneous reduction in inulin clearance is consistent with the hypothesis that H2-receptor antagonists do not exacerbate cyclosporine nephrotoxicity and lower GFR, but rather compete with creatinine for tubular secretion.     

Effect of chronic theophylline administration on amphotericin B nephrotoxicity in rats

The effect of chronic theophylline administration on amphotericin B nephrotoxicity was investigated in rats. A 7-day treatment of amphotericin B (5 mg/kg/day i.p.) significantly reduced the glomerular filtration rate (GFR) measured as inuline clearance and creatinine clearance (0.74 +/- 0.29 and 0.16 +/- 0.04 ml/min, respectively) in comparison to vehicle-treated rats (2.04 +/- 0.23 and 1.29 +/- 0.19 ml/min, respectively). The reduced GFR led to evaluations in serum creatinine and BUN concentrations (0.94 +/- 0.09 and 78 +/- 11 mg/dl) in comparison to their own values before treatment (0.45 +/- 0.11 and 19 +/- 3 mg/dl). In addition amphotericin B induced an increase in sodium and a decrease in potassium excretion, the fractional sodium excretion was elevated 50-fold. The methylxanthine, theophylline, had a beneficial effect on the outcome of amphotericin-B-induced renal failure. The inuline clearance was 1.17 +/- 0.04 ml/min, the creatinine clearance 0.43 +/- 0.03 ml/min, the serum creatinine concentration 0.76 +/- 0.05 mg/dl and the BUN concentration 40 +/- 6 mg/dl. Theophylline had no effect on total sodium excretion and potassium excretion. The fractional sodium excretion, however, improved significantly. Theophylline as well as sodium deoxycholate, the detergent of amphotericin B, given alone had no effect on renal hemodynamics measured after 7 days.     

Lipid formulations of polyene antifungal drugs and attenuation of associated nephrotoxicity

Amphotericin B is an effective broad-spectrum antifungal agent, but various side effects, especially nephrotoxicity, have restricted its use. Recently, lipid formulations of amphotericin B have been developed in order to reduce its toxic side effects. Clinical trials, although in the early stages, suggest promising results, and that some of these lipid formulations are potent and less toxic, even at higher doses. We summarize herein the existing information about newer lipid formulations of polyene antifungal drugs, which could attenuate associated nephrotoxicity.     

Akutes Nierenversagen Pathophysiologie – klinische Beurteilung – Therapie

Acute renal failure (ARF) is characterized by an acute decrease in glomerular filtration rate (GFR). ARF complicates 4% to 23% of intensive care unit admissions, and is associated with a mortality of approximately 50% among critically ill patients. In the intensive care setting the term ARF is usually applied to acute tubular necrosis (ATN), a form of intrinsic ARF caused by ischemia or nephrotoxins. Pathophysiological mechanisms involved in the decline in GFR include tubular obstruction caused by detachment of tubular epithelial cells from the basement membrane and back-leak of glomerular filtrate as a consequence of disruption of the epithelial cell layer. Vascular mechanisms involved in the pathophysiology of ATN are vasoconstriction due to an imbalance between vasoconstrictive and vasodilatory mediators and vascular obstruction caused by cell aggregation. Currently, there is no real time method to monitor renal function comparable to the real time monitoring of blood pressure or arterial oxygen saturation. Urinary output does not reflect glomerular filtration which may be critically reduced despite normal urine volumes and creatinine clearance still provides the clinically most applicable estimate of GFR. Tubular function can be assessed using the fractional excretion of sodium or the ratio of urinary and serum osmolality; both parameters can be obtained from spot samples of urine and serum and no urinary sampling period is necessary. However, both parameters are strongly affected by the administration of loop diuretics and high fluid and sodium inputs which are common in the intensive care unit. We determined the day to day variability of creatinine clearance, fractional excretion of sodium and the urinary to serum osmolality ratio in critically ill patients without renal dysfunction (i.e. creatinine clearance in the normal range) and found differences of 16% for creatinine clearance, 79% for fractional excretion of sodium and 22% for urinary to serum osmolality ratio. Treatment of ARF is mainly supportive and there is no clinically accepted therapy that attenuates the course of ATN. Treatment of the underlying disease and renal replacement therapy are the main options for the treatment of patients with ARF. In critically ill patients continuous venovenous hemo(dia)filtration is the first choice because it provides more hemodynamic and metabolic stability than intermittent therapy. Acute life-threatening hyperkalemia is an indication for intermittent hemodialysis because of the higher efficacy of dialysis in the clearance of low molecular weight substances.     

Influence of albumin dialysis on pharmacokinetics of amphotericin B colloidal dispersion and amphotericin B lipid complex

Albumin dialysis (AD) is a therapeutic option in severe cholestatic liver failure. However, it can significantly enhance drug elimination. Pharmacokinetic data on antimicrobial agents--in particular on antimycotics--administered under this clinical condition are very sparse. Therefore, amphotericin B (AMB) plasma concentrations were measured in two critically ill patients who were treated with AD because of severe cholestatic liver failure and were prescribed lipid formulated AMB--either AMB colloidal dispersion (ABCD) or AMB lipid complex (ABLC)--for suspected invasive fungal infection. AD was performed with the molecular adsorbent recirculating system (MARS). Lipid-associated and liberated AMB were separately quantified on and off AD. The clearance of the liberated AMB fraction was not essentially affected (ABLC) or moderately enhanced during AD by a factor of 2.5 (ABCD). The clearance of the lipid-formulated fraction was increased by a factor of 4 during AD (ABCD) or was similar (ABLC) on and off AD. Despite the fact that there was a four-fold higher clearance of the lipid-formulated fraction of ABCD, the clinically relevant area under the concentration time curve of the liberated AMB fraction was only moderately changed (by 37% in ABCD, 70% in ABLC) during AD. Thus, the effect of AD on lipid formulated AMB appears to be moderate. A daily dose of 5 mg/kg will probably lead to adequate plasma levels in patients on AD.     

Successful treatment of disseminated cryptococcosis in a liver transplant recipient with fluconazole and flucytosine, an all oral regimen

Amphotericin B, with or without 5-flucytosine, is currently the therapy of choice for cryptococcal infections. However, amphotericin B, is nephrotoxic and requires long-term venous access for parenteral administration. The combination of fluconazole and flucytosine is synergistic in vitro against Cryptococcus. To date, however, the efficacy of fluconazole and flucytosine for cryptococcosis in liver transplant recipients has never been reported. We report a 66-year-old liver transplant recipient with disseminated invasive cryptococcus (presenting as cryptococcal subcutaneous abscess, osteomyelitis, and serum cryptococcal antigen titer of 1:32). The administration of amphotericin B for 3 weeks led to nephrotoxicity without any clinical response (persistent abscess without change in serum cryptococcal antigen titer). Fluconazole, at a dosage equivalent to 800 mg/day administered orally, and flucytosine, also given orally, led to a clinical response and a steady decline in serum cryptococcal antigen titer, which became negative at 6 weeks of therapy. The patient remains well 18 months after therapy. No adverse effects have been attributed to fluconazole or flucytosine. This combination obviates the nephrotoxicity and the need for parenteral access required for amphotericin B infusion, and it can be administered orally. The combination of fluconazole and flucytosine warrants future controlled trials for the treatment of cryptococcal infection in liver transplant recipients. Received: 11 March 1997 Received after revision: 11 June 1997 Accepted: 19 August 1997     

Population pharmacokinetics of aminoglycosides in critically ill trauma patients on once-daily regimens

BACKGROUND: Once-daily dosing regimens of aminoglycosides are routinely used in critically ill trauma patients. However, the pharmacokinetic parameters are variable in these patients. The purpose of this study was to evaluate the pharmacokinetics of aminoglycosides in critically ill trauma patients receiving once-daily dosing regimens. METHODS: At least two aminoglycoside concentrations were measured in each patient. Population pharmacokinetic parameters were estimated on the basis of a one-compartment structural model and the program nonlinear mixed effects modeling. RESULTS: Fifty-three aminoglycoside concentrations from 19 patients were analyzed. The aminoglycoside clearance was 5.47 L/h. The mean volume of distribution was 22.2 L (0.3 L/kg). The mean half-life was 2.9 hours. Serum-aminoglycoside concentrations were undetectable for longer than 12 hours in 4 of 19 patients. Weight, age, or serum creatinine did not significantly explain the variability. CONCLUSION: There is marked variability in aminoglycoside pharmacokinetic parameters in critically ill trauma patients. This may lead to prolonged drug-free intervals. Individualized dosing of critically ill trauma patients on the basis of at least two serum-aminoglycoside concentrations seems indicated when using once-daily dosing regimens.     

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.