Amphotericin adverse reaction

Mr. Carr is receiving amphotericin B for a systemic fungal infection. Which of the following would most likely indicate to tiie nurse that Mr. Carr is experiencing an adverse reaction to amphotericin B ... 

When amphotericin B or diuretics are administered with ACTH, the potential for hypokalemia is increased. There may be an increased need for insulin or oral antidiabetic drag s in the patient with diabetes who is taking ACTH. There is a decreased effect of ACTH when the agent is administered with the barbiturates. Profound muscular depression is possible when ACTH is administered with the anticholinesterase drugp. Live virus vaccines taken while taking ACTH may potentiate virus replication, increase vaccine adverse reaction, and decrease the patient s antibody response to the vaccine... 

Amphotericin B is obtained from Streptomyces nodosus. It is fungistatic and administered intravenously as an infusion in the treatment of severe systemic fungal infections. It also is used for the local treatment of superficial candidiasis. Test-dose administration is advised to confirm adverse reactions. The amphotericin infusion should be slow to prevent the risk of irritation and infusion-related adverse effects. The drug is used in pregnancy without any adverse side effects.66... 

Adverse reactions, particularly renal toxicity, are limiting factors in achieving an effective dose with conventional amphotericin B (see Table 11-14). 

Adverse reactions include neutropenia and thrombocytopenia which are usually but not always reversible after withdrawal. Concomitant use of potential marrow-depressant drugs, e.g. cotrimox-azole, amphotericin B, zidovudine, should be avoided. Other reactions are fever, rash, gastrointestinal symptoms, confusion and seizure (the last especially if imipenem is coadministered). 

Amiloride is a therapeutic option in reducing potassium losses in patients receiving amphotericin. When it was given to 19 oncology patients with marked amphotericin-induced potassium depletion mean serum potassium concentrations increased in the 5 days before and after administration (from 3.4 to 3.9 mmol/1) (8). There was also a trend toward reduced potassium supplementation (48 versus 29 mmol/day). Adverse reactions were limited to hyperkalemia in two patients who took amiloride 20 mg/day and a high potassium intake. 

In pharmaceutical preparations, soybean oil emulsions are primarily used as a fat source in total parenteral nutrition (TPN) regimens. Although other oils, such as peanut oil, have been used for this purpose, soybean oil is now preferred because it is associated with fewer adverse reactions. Emulsions containing soybean oil have also been used as vehicles for the oral and intravenous administration of drugs drug substances that have been incorporated into such emulsions include amphotericin, " diazepam, retinoids, vitamins, poorly water-soluble steroids, fluorocarbons, and insulin. In addition, soybean oil has been used in the formulation of many drug delivery systems such as liposomes, microspheres, dry emulsions, self-emulsifying systems, and nanoemulsions and nanocapsules. ... 

Tile usefulness of amphotericin B is limited by a high prevalence of adverse reactions. Nearly 80% of patient-treated with amphotericin B develop nephrotoxicity. Fever headache, anorexia, gastrointestinal distress, malaise, and muscle and joint pain arc common. Pain at the site of injection and thrombophlebitis are frequent complications of intravenous administration. The drug must never be administered intramuscularly. The hemolytic activity of amphotericin B may be a consequence of its ability to Icadi cholesterol from erythrocyte cell membranes. 

Systemic fungal diseases (e.g. histoplasmosis and blastomycosis) are uncommon but, if untreated, often fatal. They usually take the form of lung infections or meningitis. The best treatment is still the polyene antibiotic, amphotericin B 5.14) whose mode of action is described in Section 5.4.1 (p. 192). It is usually administered intravenously. Flucytosine 4.23) is an excellent synergist (Section 4.0, p. 131), seldom given alone. Intravenous miconazole 6.23) provides alternative therapy, but there are frequent adverse reactions. An orally active analogue, ketoconazole ( Nizoral ) was introduced in 1981, and looks promising. 

Systematic reviews In a systematic review and meta-analysis of 39 randomized controlled trials in more than 8000 patients, the incidence rates of treatment discontinuation owing to adverse reactions in general and liver damage in particular associated with antifungal therapy varied widely [d ]. The pooled risks of treatment withdrawal because of adverse reactions were over 10% for amphotericin B and itraconazole and 2.5-3.8% for fluconazole, caspofungin, and micafimgin. 

Observational studies Adverse reactions to amphotericin B deoxycholate have been studied in a retrospective analysis of 39 courses of treatments in 33 Chilean patients 1% On average, therapy lasted 12 (range 2-39) days and the cumulative dose was 600 (100-1950) mg. In 63% of cases 24-hour infusions were used and 36% received a 4-to 6-hour infusion. In addition, 37% received daily an infusion of saline before amphotericin. There were adverse reactions in 40% of treatments fever was the most common (25%). Nephrotoxicity was relatively infrequent (9.4%), and it affected only patients without previous renal disease and not requiring dialysis. Hypokalemia developed in 22% of treatments. In a multivariate analysis, age over 60 years was an independent factor for infusion-related adverse reactions and a Sequential Organ Failure Assessment (SOFA) score over 3 and glucocorticoid administration at the same time as amphotericin were independently associated with fatal outcomes. 

Drug administration route In a prospective study of the disposition of nebulized amphotericin B Upid complex, 1 mg/kg every 24 hours for 4 days in 35 lung transplant recipients, satisfactory concentrations were achieved in the bronchial epitheUal lining fluid with only low concentration in the plasma [8 ]. Adverse reactions to nebulized amphotericin included wheezing, coughing, and a 12% fall in FEVi. 

Management of adverse reactions Administration of amphotericin B lipid complex (ABLC) may be associated with infusion-related reactions, such as fever, rigors, and chills. Premedication with hydrocortisone may reduce the incidence of these reactions, but there are currently limited confirmatory data from clinical practice [7 ]. In a prospective 18-month study, patients with cancers were given intravenous hydrocortisone 100 mg 15-30 minutes before each infusion of ABLC (275 cycles mean dose per cycle 931 mg) [14. There were 44 infusion-related reactions (16%), most of which followed the first infusion of a cycle (15% subsequent infusions 2.9%). The most common reactions were rigors (15%) and fever (13). There was no significant difference in the rates or types of reactions between ABLC-naive and previously treated patients. The dose of ABLC had no effect on the rate of reactions, but female sex, neutropenia, and being younger were predictive. 

The clinical usefulness of amphotericin B in the treatment of systemic mycoses is limited by its toxicity profile. Acute adverse reactions during and in the immediate postinfusion period include nausea, vomiting, headache, fever and chills. Thrombophlebitis at the infusion site is also a... 

Amphotericin B is the mainstay of treatment of patients with severe endemic fungal infections. The conventional deoxycholate formulation of the drug can be associated with substantial infusion-related adverse effects (e.g., chills, fever, nausea, rigors, and in rare cases hypotension, flushing, respiratory difficulty, and arrhythmias). Pre-medication with low doses of hydrocortisone, acetaminophen, nonsteroidal anti-inflammatory agents, and meperidine is common to reduce acute infusion-related reactions. Venous irritation associated with the drug can also lead to thrombophlebitis, hence central venous catheters are the preferred route of administration in patients receiving more than a week of therapy. 

The primary adverse effect of intravenous cidofovir is a dose-dependent nephrotoxicity. Concurrent administration of other potentially nephrotoxic agents (eg, amphotericin B, aminoglycosides, nonsteroidal anti-inflammatory drugs, pentamidine, foscarnet) should be avoided. Prior administration of foscarnet may increase the risk of nephrotoxicity. Other potential side effects include uveitis, decreased intraocular pressure, and probenecid-related hypersensitivity reactions. Neutropenia and metabolic acidosis are rare. The drug caused mammary adenocarcinomas in rats and is embryotoxic. 

Aspirin, paracetamol, and hydrocortisone are used to control febrile reactions of amphotericin. Patients with a history of adverse effects with amphotericin should be prophylactically treated with antipyretics and hydrocortisone. Antiemetics and pethidine also are used for the treatment of adverse effects of amphotericin. With sodium supplements and hydration therapy, damage to the kidney can be reduced. If conventional amphotericin is not well tolerated by the patient, colloidal carriers can be used as alternative options. Administration of amphotericin with a nephrotoxic drug, such as cyclosporin, may further increase toxicity. Diuretics and anticancer drugs should be avoided with amphotericin. 

To enable reduction of the dose of one component and hence reduce the risks of adverse drug reactions, e.g. flucytosine plus amphotericin B for Cryptococcus neoformans meningitis. 

The safety and efficacy of ABLC 5 mg/kg/day in patients with neutropenia and intolerance or refractoriness to amphotericin deoxycholate have been reported in two smaller series of 25 treatment courses from the UK. In one, the mean serum creatinine at the start of therapy was 139 pmol/l and at the end of therapy 132 pmol/l there were no infusion-related adverse events (27). There was an increase in alanine transaminase activity in 12 of the 22 analysed treatment courses. In the other, there was an increase in serum creatinine in 5 of 18 courses (28%), and hypokalemia (less than 2.5 mmol/1) in two courses (11%) premedication for infusion-associated reactions was required in three courses (17%) (28). There were modest increases in serum alanine transaminase activities in five patients (30%). 

Amphotericin deoxycholate in glucose versus amphotericin in nutritional fat emulsion The safety of DAMB prepared in nutritional fat emulsion (a non-approved mode of amphotericin administration) has been reviewed (SEDA-21, 282) (SEDA-22, 285). It is not clear whether it has a better therapeutic index than other formulations, and methods of preparing it have not been standardized. The adverse effects of amphotericin prepared in nutritional fat emulsion have been compared with those of amphotericin prepared in 5% dextrose in two studies. While one of the studies showed a significantly lower frequency of infusion-related reactions and hypokalemia in patients receiving the fat emulsion (49), there were no differences in safety and tolerance between the two formulations in the other study (50). The safety of amphotericin prepared in nutritional fat emulsions has been reviewed (SEDA-21, 282) (SEDA-22, 285). Because of stability concerns and lack of systematic safety data, this form of amphotericin cannot be recommended. 

Anaphylaxis after ABCD occurred in a patient who had previously been treated with both amphotericin deoxycholate and ABLC without infusion-related adverse effects (65). During the first infusion of ABCD he developed spontaneously reversible severe back pain and then swelling of his lips, respiratory distress, and left-sided hemipar-esis, which resolved after 24 hours. An MRI scan suggested an ischemic event in the right putamen, lending support to the hypothesis that he had had an anaphylactic reaction to ABCD, hypoperfusion, and a subsequent stroke. 

Cook G, Franklin IM. Adverse drug reactions associated with the administration of amphotericin B hpid complex (Abelcet). Bone Marrow Transplant 1999 23(12) 1325-6. 

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