Nephrotoxicity amphotericin

The irreversible form of amphotericin nephrotoxicity usually occurs in the setting of prolonged administration (> 4 g cumulative dose). Renal toxicity commonly presents with renal tubular acidosis and severe potassium and magnesium wasting. There is some evidence that the prerenal component can be attenuated with sodium loading, and it is common practice to administer normal saline infusions with the daily doses of amphotericin B. 

Costa S, Nucci M. Can we decrease amphotericin nephrotoxicity Curr Opin Crit Care 2001 7 379-83. 

Amphotericin nephrotoxicity is best treated by discontinuation of therapy and substitution of alternative antifungal therapy, if possible. Renal tubular dysfunction and glomerular filtration will improve gradually to some degree in most patients, but damage may be irreversible. 

Amphotericin B (15) is an antifimgal macioHde antibiotic produced by Streptomjces nodosus that has been used as an alternative, albeit more toxic, dmg to the antimonials. It acts as a leishmanicide against the visceral and mucocutaneous forms of the disease. To overcome its potentially severe nephrotoxicity, the dmg must be adrninistered over an extended period of time. 

An additive nephrotoxicity develops when pentamidine isethionate is administered with other nephrotoxic drugs (eg, aminoglycosides, vancomycin, or amphotericin B). An additive bone marrow depression occurs when the drug is administered with antineoplastic drugs or when the patient lias received radiation therapy recently. 

Amphotericin B-induced ARF occurs in as many as 40% to 65% of patients treated with the conventional desoxycholate formulation.30 Nephrotoxicity is due to renal arterial vasoconstriction and distal renal tubule cell damage. Risk factors include high doses, treatment for at least 7 days, preexisting kidney dysfunction, and concomitant use of other nephrotoxic drugs.31 Three lipid-based formulations of amphotericin B have been developed in an attempt to decrease the incidence of ARF amphotericin B lipid complex, amphotericin colloidal dispersion, and liposomal amphotericin B. The range of... 

Determine if drug therapy may be contributing to ARF. Consider not only drugs that can directly cause ARF (e.g., aminoglycosides, amphotericin B, NSAIDs, cyclosporine, tacrolimus, ACE inhibitors, and ARBs), but also drugs that can predispose a patient to nephrotoxicity or prerenal ARF (i.e., diuretics and anti hypertensive agents). 

However, it is important to note that the addition of nephrotoxic agents, such as amphotericin B, aminoglysides (e.g., gentamicin, tobramidn, or amikacin), and non-steroidal anti-inflammatory drugs (NSAIDs e.g., naproxen, ibuprofen, or ketorolac) may potentiate the nephrotoxic effects of the calcineurin inhibitors. 

Treatment fluconazole, itraconazole, ketoconazole, Amphotericin B Consider liposomal products decrease or stop CSA or TAC to minimize nephrotoxicity Remember to adjust doses of renally eliminated drugs (e.g., acyclovir, ganciclovir, TMP-SMX)... 

Response to antifungal therapy in invasive candidiasis is often more rapid than for endemic fungal infections. Resolution of fever and sterilization of blood cultures are indications of response to antifungal therapy. Toxicity associated with antifungal therapy is similar in these patients as described earlier with the caveat that some toxicities maybe more pronounced in crit-ically-ill patients with invasive candidiasis. Nephrotoxicity and electrolyte disturbances, with amphotericin B in particular, are problematic and may not be avoidable even with lipid amphotericin B formulations. Fluconazole and echinocandins are generally safer options, and are generally well tolerated. Decisions to use one class of agents over the other is principally driven by concerns of non-albicans species, patient tolerability, or history of prior fluconazole exposure (risk factor for non-albicans species.). 

Liposomal amphotericin B 3 mg/kg IV daily Lower incidence of nephrotoxicity and infusion reactions more expensive. 

In patients who cannot tolerate voriconazole, amphotericin B can be used. Full doses (1 to 1.5 mg/kg/day) are generally recommended, with response measured by defervescence and radiographic clearing. The lipid-based formulations may be preferred as initial therapy in patients with marginal renal function or in patients receiving other nephrotoxic drugs. The optimal duration of treatment is unknown. 

Amphotericin B nephrotoxicity can be reduced by slowing the infusion rate to 24 hours or, in at-risk patients, substituting liposomal amphotericin B. 

B. Related to synergistic nephrotoxicity. Aminoglycosides in combination with Amphotericin B... 

Renai function impairment Use amphotericin B desoxycholate with care in patients with reduced renal function frequent monitoring is recommended (see Precautions). Lipid formulations have been reported to overcome most problems of chronic nephrotoxicity, even in patients with impaired renal function following previous treatment with amphotericin B desoxycholate. 

Drugs that may interact with foscarnet include nephrotoxic drugs (eg, aminoglycosides, amphotericin B, IV pentamidine), pentamidine, and zidovudine. Foscarnet decreases serum levels of ionized calcium. Exercise particular caution when other drugs known to influence serum calcium levels are used concurrently. 

Drugs that may affect tacrolimus include nephrotoxic agents (aminoglycosides, amphotericin B, cisplatin, cyclosporine), antifungals, bromocriptine, calcium channel blockers, cimetidine, clarithromycin, danazol, diltiazem, erythromycin, methylprednisolone, metoclopramide, carbamazepine, phenobarbital, phenytoin, rifamycins, cisapride, chloramphenicol, metronidazole, nefazodone, omeprazole, protease inhibitors, macrolide antibiotics, fosphenytoin, and St. John s wort. 

Amphotericin B Cholesteryl (Amphotec) [Antifungal/Polyene Mocrollde] Uses AspCTgillosis if intolCTant/refractory to conventional amphotericin B, systemic candidiasis Action Binds ceU membrane sterols, alters permeability Dose Adults Peds. Test dose 1.6—8.3 mg, over 15-20 min, then 3-4 mg/kg/d 1 mg/kg/h inf w/ renal insuff Caution [B, ] Disp Inj SE Anaphylaxis fever, chills, HA, nephrotox, -1- BP, anemia Notes Do not use in-line filter Interactions See Amphotericin B EMS See AmphotCTicin B OD May cause cardiac arrest s ptomatic and supportive... 

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. 

The severity of aminoglycoside nephrotoxicity is additive with that of vancomycin, polymixin, gallium, furosemide, enflurane, cisplatin, and cephalosporins. Aminoglycoside nephrotoxicity is synergistic with that of amphotericin B and cyclosporine. 

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