Amphotericin adverse effects

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. 

Nephrotoxins (N) orototoxins (0) (eg., amphotericin B (N), cisplatin (N/0), cyclosporine (N), furosemide (0), NSAIDs (N), radio contrast (N), vancomycin (N) Additive adverse effects Monitor aminoglycoside SDC and renal function... 

Amphotericin B Azoles Nephrotoxins (e.g, aminoglycosides, cidofovir, cyclosporine, foscarnet, pentamidine) See Chap. 125 in Pharmacotherapy A Pathophysiologic Approach, seventh edition, page 1998. Additive adverse effects Monitor renal function... 

Treatment of candidiasis is presented in Table 38-4. Amphotericin B may be switched to fluconazole (IV or oral) for completion of therapy. Azoles and deoxycholate amphotericin B are similarly effective however, fewer adverse effects are observed with azoles. Echinocandins are at least as effective as amphotericin B or fluconazole in nonneutropenic adult patients with candidemia. 

Amphotericin-B is highly toxic as ergosterol is very similar to cholesterol and amphotericin has thus cross-reactivity to cholesterol in human cell membranes. Adverse effects include chills, fever, dyspnea, hepatotoxicity and anemia. However, nephrotoxicity is the most common complication, although adequate hydration can reduce the risk for this toxicity to some extend. Amphotericin induced nephrotoxicity may be irreversible. Liposomal preparations have shown to be therapeutically effective with little or no renal damage. 

B. Amphotericin B remains the drug of choice in the treatment of disseminated or invasive fungal infections in immunocompromised hosts bone marrow transplant recipients are the most heavily immunocompromised patients encountered in the hospital setting. 5-Flucytosine has no significant activity against Aspergillus spp., and it has bone marrow toxicity as a common adverse effect it should... 

Flucytosine is converted into the anti metabolite 5-fluorouracil that inhibits thymidilate synthetase, thereby disrupting DNA synthesis. It also interferes with protein synthesis by incorporation of fluorouracil into RNA in place of uracil. Although active against most Candida species, its spectrum of antifungal activity, overall, is narrow. Since resistance can develop rapidly it is usually coadministered with another agent and its main value is that it facilitates a reduction in the dose (and, presumably, the toxic effect) of amphotericin when co-prescribed in this way. The main adverse effects are marrow aplasia and hepatotoxicity. 

Adverse effects associated with oral administration of nystatin include mild nausea, diarrhea, and occasional vomiting. Topical application is nonirritating, and allergic contact hypersensitivity is exceedingly uncommon. Topical amphotericin is well tolerated and only occasionally locally irritating. Hypersensitivity is rare. The drug may cause a temporary yellow staining of the skin, especially when the cream vehicle is used. 

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. 

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... 

All patients receiving amphotericin intravenously suffer from nephrotoxicity. In nonconventional dosage forms, such as liposomal formulations, the adverse effects are similar but less toxic when compared with conventional dosage. 

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. 

Amifostine Amifostine is incompatible with many drugs such as acyclovir sodium, amphotericin, cefoperazone sodium, hydroxyzine hydrochloride, miconazole, minocycline hydrochloride, and prochlorpherazine edisylate.239 Care should be exercised when handling amyl nitrate, since it is highly flammable. Volatile nitrites, such as poppers, are abused and fatal adverse effects are reported.240,241... 

Adverse effects Amphotericin B has a low therapeutic index. A total daily dose should not exceed 1.5 mg/kg. Small test doses are usually administered to assess the degree of a patient s negative response, for example, anaphylaxis or convulsions. Other toxic manifestations include the following ... 

Nystatin [nye STAT in] is a polyene antibiotic its structure, chemistry, mode of action, and resistance resemble those of amphotericin B. Its use is restricted to topical treatment of Candida infections because of its systemic toxicity. The drug is negligibly absorbed from the gastrointestinal tract, and it is never used par-enterally. It is administered as an oral agent ( swish and swallow ) for the treatment of oral candidiasis. Excretion in the feces is nearly quantitative. Adverse effects are rare because of its lack of absorption, but occasionally nausea and vomiting occur. 

Caspofungin is a cyclic polypeptide that inhibits synthesis of the fungal cell wall. It can be used in systemic mycoses due to as-pergillus fungi when amphotericin B or itroconazole cannot be employed. It is given by infusion and causes various adverse effects. 

AMPHOTERICIN NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS - TENOFOVIR, ZIDOVUDINE Possibly T adverse effects with tenofovir and zidovudine Additive toxicity Avoid if possible otherwise monitor FBC and renal function (weekly). 1 doses as necessary... 

Normally, reconstituted amphotericin B solutions are administered by slow infusion over a period of six hours (minimum one to two hours) to avoid potentially serious adverse effects. The manufacturers state that during administration the IV infusion solutions should be "protected from light." Photoprotection during administration is not required for ampothericin B cholesteryl sulfate complex, amphotericin B lipid complex, or liposomal formulations of amphotericin B. The administration of amphotericin B in parenteral fat emulsions is no longer an accepted practice. 

Flucytosine (5-fluorocytosine) is metabolised in the fungal cell to 5-fluorouracil which inhibits nucleic acid synthesis. It is weU absorbed from the gut, penetrates effectively into tissues and almost all is excreted unchanged in the urine (t) 4 h). The dose should be reduced for patients with impaired renal function, and the plasma concentration should be monitored. The drug is well tolerated when renal function is normal. Candida albicans rapidly becomes resistant to flucytosine which ought not to be used alone it may be combined with amphotericin (see Table 14.2) but this increases the risk of adverse effects (leucopenia, thrombocytopenia, enterocolitis) and it is reserved for serious infections where the risk-benefit balance is favourable (e.g. Cryptococcus neoformans meningitis). 

In an open, sequential phase II clinical study of three different regimens of liposomal amphotericin for visceral leishmaniasis (2 mg/kg on days 1-6 and on day 10 2 mg/ kg on days 1-4 and on day 10 2 mg/kg on days 1, 5, and 10) in Indian and Kenyan patients in three developing countries, there were few infusion-associated adverse effects (40). Of 32 Brazilian patients (15 of whom received 2 mg/kg on days 1-10 because of poor responses to the first regimen, 37% had a fever with one or more infusions, 9% had chills, and 6% had back pain in addition, three patients had respiratory distress and/or cardiac dysrhythmias. There were different response rates to the three regimens in the different countries, leading to the recommendation of 2 mg/kg on days 1-4 and day 10 in India and Kenya, and 2 mg/kg on days 1-10 in Brazil. 

The efficacy and tolerability of amphotericin prepared in Intralipid 20% have been evaluated in 16 patients with HIV infection and esophageal candidiasis or cryptococcosis and compared with standard amphotericin in a matched group of 24 patients (44). While both formulations had apparently similar clinical and microbiological efficacy, fewer patients receiving the lipid emulsion formulation required premedication or symptomatic therapy for infusion-associated adverse events, and fewer patients were withdrawn because of adverse effects. Renal adverse effects (a rise in serum creatinine and/or electrolyte loss) were more common in patients who received the conventional formulation. 

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. 

This case shows that, regardless of the formulation of amphotericin, severe neurological adverse effects can occur, in particular in patients who receive large dosages of amphotericin after cranial irradiation. A clinical syndrome of akinetic mutism, incontinence, and parkinsonism has been described in patients who received large doses of amphotericin deoxycholate in association with central nervous system irradiation or infection (67). 

Continuous infusion of amphotericin has been assessed in an open study in six lung transplant recipients with invasive or semi-invasive bronchopulmonary azole-resistant candidal infections who were treated for 40 (17-73) days by 24-hour continuous infusions of amphotericin 1 mg/kg (113). They received at least 1000 ml/day of 0.9% saline intravenously. Apart from ciclosporin, five patients received aminoglycosides for at least 2 weeks, and four received ganciclovir. Calculated creatinine clearance fell from 57 (43-73) ml/minute to a nadir of 35 (28-39) and recovered to 52 (33-60) after the end of therapy. One patient needed temporary hemofiltration for 7 days. Besides three episodes of mild hypokalemia there were no adverse effects attributable to amphotericin. Asymptomatic colonization with Candida persisted for 10 months in one case, but the other five patients were cured. 

---