best practice guidelines for the management of adverse events associated with amphotericin b lipid...

1. Introduction

2. Search strategy and selection

criteria

3. Management of drug delivery

reactions

4. Preserving renal function

5. Audit criteria

6. Conclusion

7. Expert opinion

Review

Best practice guidelines for themanagement of adverse eventsassociated with amphotericin Blipid complexCharles Craddock†, James Anson, Patrick Chu, Andrew Dodgson,Nick Duncan, Cesar Gomez, Jayesh Mehta, Shalal Sadullah,Chinari Subudhi & John-Liu Yin†Queen Elizabeth Hospital, Birmingham, UK

Importance of the field: Amphotericin B lipid complex is a widely used lipid-

based formulation of amphotericin B, which has a broad spectrum of activity

against a variety of fungal pathogens. It has also been shown to be signif-

icantly less nephrotoxic than conventional amphotericin B. However, infu-

sional drug reactions, similar to those seen when using conventional

amphotericin B, have been reported in a significant number of patients, so

it is important that these are prevented or managed effectively, particularly in

light of the changing epidemiology of systemic fungal infections.

Areas covered in this review: This article reviews effective strategies that can

be used to reduce the risk of drug delivery reactions associated with ampho-

tericin B lipid complex. Preserving renal function and managing spikes in

serum creatinine levels are also discussed.

What the reader will gain: The aim of this paper is to provide healthcare

professionals with clear guidance on the management of adverse events

associated with amphotericin B lipid complex. Recommendations are based

upon the published evidence and clinical experience from a number of

different centres.

Take home message: Amphotericin B lipid complex represents a valu-

able therapeutic option in the treatment of fungal infections but impro-

ved strategies for the management of infusion-related adverse events

are required.

Keywords: amphotericin B, fungal infections, guidelines, lipid complex, management

Expert Opin. Drug Saf. (2010) 9(1):139-147

1. Introduction

Over the last few years, lipid-based formulations of amphotericin B have beendeveloped both to reduce the toxicity of conventional amphotericin B and toimprove its tissue distribution [1]. Amphotericin B lipid complex or ABLC(Abelcet�, Cephalon UK Ltd) is a widely used lipid-based formulation that showsa broad spectrum of activity against a variety of fungal infections includingaspergillosis, zygomycosis, fusariosis and candidiasis [1-4]. At its recommendeddose of 5 mg/kg/day, ABLC has been shown to be effective in the treatment ofinvasive fungal infections in immunocompromised patients who are refractory to, orintolerant of, conventional amphotericin B, including those with haematologicmalignancies [1-3], neutropaenia [5], AIDS [2], and solid organ or haematopoieticstem cell transplant (HSCT) recipients [2,5]. In addition to ABLC, two other lipid-based formulations of amphotericin B have been developed and are widely used inmany countries: liposomal amphotericin B (LAB; AmBisome�, Gilead Sciences Ltd)

10.1517/14740330903418430 © 2010 Informa UK Ltd ISSN 1474-0338 139All rights reserved: reproduction in whole or in part not permitted

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and amphotericin B colloidal dispersion (ABCD; Amphocil�/Amphotec�, Three Rivers Pharmaceuticals) [6]; however, thefocus of this review is ABLC.The safety profile of ABLC is improved compared with

conventional amphotericin B. In clinical trials, it has beenshown to be significantly less nephrotoxic than conventionalamphotericin B, and as a result is considered an importantstrategy to preserve renal function and improve survival incritically ill patients who require treatment for systemic fungalinfections [7]. ABLC is generally tolerated well in adults [1-3,5]

and children [4,8], with mild to moderate side effects. The mostcommonly reported adverse effects are transient drug deliveryreactions (DDRs), such as fever and chills, which occurparticularly at the beginning of therapy and generally diminishin subsequent infusions [3,9]. These adverse reactions are notdose-limiting and are manageable with the use of premedica-tion or by changing the duration of the infusion [3,9]. Theprevention, early identification and management of DDRs,however, is paramount, especially in light of the increasingpopulation at risk of fungal infections and the changingspectrum of invasive mycoses [10,11].The aim of this review is to provide recommendations for

the management of adverse events associated with ABLC, witha particular focus on strategies aimed at preventing or reducingthe risk of DDRs and practical guidance on managing spikesin serum creatinine levels.

2. Search strategy and selection criteria

A systematic review of the published literature was undertakento evaluate the best evidence available on the optimal admin-istration of ABLC and the management of DDRs and renalside effects. The initial search, using a combination of freetext terms, ‘Amphotericin B lipid complex’, ‘Abelcet’,‘AmBisome’, ‘Nephrotoxicity’ and ‘Infusion related reactions’,was undertaken using PubMed. The search results weresupplemented by an assessment of bibliographies of recentreviews to ensure the capture of all relevant data. A consensuspanel of clinicians from various centres around the UK, withpractical experience of using ABLC, was convened in order toreview the evidence and share details of best practice. Recom-mendations on the optimal management of adverse eventsassociated with ABLC and the algorithm that follow have beenmade based on this review of the literature and the personalexperiences of the consensus panel. The grading system chosenfor this guideline is that developed by the North of Englandevidence-based guidelines development project [12]. Thestrength of evidence supporting each recommendation is givenin Table 1.

3. Management of drug delivery reactions

Transient DDRs, such as fever and chills, similar to those seenwhenusing conventional amphotericinB, have been reported inclinical trials of ABLC, albeit at a lower rate than with

conventional amphotericin B [3,4,9]. These reactions are usuallymore common with the initial infusion and generally decreasewith subsequent infusions [3,9].DDRshave alsobeen reported tooccurwith other lipid-based formulations of amphotericinB [6].Clinical trials have indicated thatABCD is associatedwithmoreDDRs than conventional amphotericin B [13,14], whereasLAB has a lower rate of DDRs than both conventionalamphotericin B and, to a lesser extent, ABLC [5,15].

DDRs have been linked to the ability of amphotericin-containing drugs to induce the release of inflammatory cyto-kines such as IL-1 and TNF a by mononuclear cells [16]. Theactions of these cytokines may cause an alteration in thehypothalamic set-point of the brain, leading to fever andchills [17,18]. In order to improve the management of patientswith invasive fungal infections and increase the therapeuticutility of ABLC, several strategies have been used to reduce therisk of DDRs (Table 2).

3.1 PremedicationIn an attempt to reduce the incidence of DDRs that areassociated with the use of conventional amphotericin B andlipid-based formulations, a number of different pretreatmentregimens have been used, including corticosteroids, NSAIDs,aspirin, acetaminophen, dantrolene and narcotic analgesics [19].However, there is great variability in drugs and regimenschosen by physicians for the prevention of DDRs. Further-more, until recently, there has been a paucity of data on theeffectiveness of these pretreatment regimens [9]. To addressthis issue, two large audits have recently been under-taken [20,21], one of which was a prospective audit thatspecifically evaluated the effect of hydrocortisone premedica-tion on DDRs following ABLC infusion [20]. In this study byO’Connor and Borley [20] all cancer patients treated withABLC over an 18-month period were audited prospectively.Patients received 100 mg of intravenous hydrocortisone15 – 30 min before each ABLC infusion. A total of 275cycles of ABLC at a mean dosage of 930.6 mg were admin-istered during the course of the study. The incidence of DDRsfollowing premedication with hydrocortisone is shownin Table 3. In total, 16% were associated with DDRs, noneof which was serious. The majority of reactions occurredduring the first infusion and resolved in subsequent infusionswhere the DDR rate per cycle decreased to 2.9%. BothABLC-naive and previously treated patients were includedin the study and no significant difference in the DDR rate wasobserved between the two groups (17.2 versus 15.5% per cycleand 4.1 versus 2.9% per infusion, respectively; p = 0.231).In addition, the rate of DDRs did not differ significantlywhen patients were treated with different dosages (100,200 or ‡ 300 mg) of ABLC for their initial infusion. In amultivariate analysis, female gender, being neutropaenic anddecreasing (younger) age were found to be predictive of havinga DDR. Overall, these results suggest that premedicationwith hydrocortisone prior to ABLC infusion can significantlyreduce DDRs, especially because the incidence is substantially

Best practice guidelines for the management of adverse events associated with amphotericin B lipid complex

140 Expert Opin. Drug Saf. (2010) 9(1)

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lower than that reported by Wingard et al. [5] where nopremedication was allowed prior to the first infusion.

These findings are consistent with observations from aretrospective cost-minimisation analysis of ABLC and LAB(mean daily dosage 4.3 mg/kg for both drugs) undertakenby Kuti et al. [22]. In this study, the majority of patients(ABLC: 89%; LAB: 88%) received premedication, primarilywith paracetamol or diphenhydramine or both, 30 min prior totherapy being given. Other prophylactic agents used includedibuprofen, hydrocortisone and pethidine. A lower rate ofDDRs was observed for the ABLC-treated group comparedwith the LAB-treated group (11 versus 24%, respectively),although this did not reach statistical significance. The authorssuggest that the incidence of DDRs in each group may havebeen due to the similar percentage of patients receivingpremedication to prevent or reduce DDRs in both groups [22].

A number of other clinical trials have demonstrated that,although not usually used, subsequent premedication withcorticosteroids or antihistamines following a DDR to ABLCcan prevent further systemic adverse reactions [1,3,23,24]. In astudy by Mehta et al. [1] the efficacy and tolerability of ABLCat a dose of 5 mg/kg/day was evaluated for the treatment ofconfirmed or presumed fungal infections in 64 immunocom-promised patients with haematologic malignancies. Followingthe development of febrile reactions in seven patients anddiscontinuation of ABLC therapy after a single dose in five ofthese patients, premedication was subsequently given to allpatients with a previous history of reactions to conventionalamphotericin B and no further DDRs were observed.Clevenbergh et al. [24] also observed that DDRs were con-trolled during subsequent infusions of ABLC at an initial doseof 5 mg/kg/day for the treatment of proven or suspectedinvasive fungal infection in patients who were intolerant of orfailing conventional amphotericin B by the administration oflow doses of corticosteroids, paracetamol or pethidine.

These findings are corroborated in a multi-centre, open-label, non-comparative study of 93 patients who receivedABLC 5 mg/kg/day, where adverse events were generallymild or moderate and were controlled effectively with theuse of appropriate premedication, although no details of thepretreatment regimens were given [23]. Furebring et al. [9] alsoreported that DDRs, such as fever and chills, were mostpronounced at the beginning of ABLC therapy, but tendedto level off after repeated administration, and were adequatelycontrolled with pethidine premedication. Similarly, in a

Table 1. Category of evidence and strength of recommendations.

Category of evidence

Ia Evidence from meta-analysis of randomised controlled trials

Ib Evidence from at least one randomised controlled trial

IIa Evidence from at least one controlled trial without randomisation

IIb Evidence from at least one other type of open label study

III Evidence from descriptive studies, such as comparative studies, correlation studies and case-control studies

IV Evidence from expert committee reports or opinions or clinical experience of respected authorities, or both

Strength of recommendations

A Directly based on category I evidence

B Directly based on category II evidence or extrapolated recommendation from category I evidence

C Directly based on category III evidence or extrapolated recommendation from category I or II evidence

D Directly based on category IV evidence or extrapolated recommendation from category I, II or III evidence

Table 2. Strategies used to minimise DDRs.

Premedication With corticosteroids, acetaminophen, pethidine, chlorphenamine or NSAIDs

Rate of infusion Slowing down the infusion rate and increasing the duration of infusion

Timing of infusion Infusing during the day and after any concomitant corticosteroids that the patients may be getting as partof their ongoing treatment

DDR: Drug delivery reaction.

Table 3. Incidence of DDRs following premedication with

hydrocortisone [20].

DDR rate per cycle (%)

Overall DDR rate 16

Following initial infusion (275 cycles) 15.3

ABLC-naive patients (99 cycles) 16.2

Previously treated patients (174 cycles) 14.9

Following subsequent infusions 2.9

ABLC: Amphotericin B lipid complex; DDR: Drug delivery reaction.

Craddock, Anson, Chu, Dodgson, Duncan, Gomez, Mehta, Sadullah, Subudhi & Yin

Expert Opin. Drug Saf. (2010) 9(1) 141

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randomised, open-label, ascending-dose design study of ABLCin the treatment of AIDS-associated cryptococcal AIDS,Sharkey et al. [25] observed that DDRs decreased by the seconddosing, coinciding with the use of premedication.Data also suggest that premedication with hydrocortisone,

diphenhydramine, pethidine and/or acetaminophen prior tolower doses of ABLC (£ 3 mg/kg/day) results in a low incidenceof DDRs [26-28].Martino et al. [27] reported that ABLC 3mg/kg/day was well tolerated in patients with a haematological malig-nancy and prolonged neutropaenia, with only 4% of infusionsfollowed by a DDR. All patients were routinely premedicatedwithdiphenhydramine andhydrocortisone, although the dose ofthese pretreatment regimens was not reported. These reactionsoccurred during the first infusion, were judged as mild by thetreating physician and consequently resolved in later infusions.A low rate of DDRs (15%) was also observed in a later study byMartino et al., [28] in which premedication with 25 – 50 mgdiphenhydramine and 100 mg hydrocortisone and/or 25 mgpethidine and/or 1 g acetaminophen was routinely given,compared to those reported in studies using higher doses andwith no initial premedication [5].Conversely, Subira et al. [29] observed a higher overall rate of

DDRs in neutropaenic patients with haematological malig-nancies and fever of unknown origin despite premedication.In this randomised controlled trial, 105 patients receivedeither ABLC 1 mg/kg/day or conventional amphotericin B0.6. Premedication with 500 mg acetaminophen and 50 mgdiphenhydramine was given to all patients in both treatmentgroups. If a DDR occurred, 25 mg pethidine and/or 50 mghydrocortisone were added to subsequent premedications.Overall, ABLC was well tolerated. There were no statisticallysignificant differences between the two treatment groups inthe overall rate of DDRs (ABLC: 73%; conventional ampho-tericin B: 77%). Although not statistically significant, feverand moderate to severe chills or rigors were more frequent inthe conventional amphotericin B group compared with theABLC group (20 versus 13%, respectively, and 11 versus 2%,respectively). The study drug was not discontinued because ofDDRs in any patient in the ABLC group and in onlytwo patients in the conventional amphotericin B group [29].

3.1.1 Key statements and recommendations

. DDRs related to the administration of ABLC are generallymild or moderate (C III)

. DDRs are most prevalent during the initial infusion andusually resolve in subsequent infusions (C III)

. All patients should be closely monitored for any type ofDDR associated with ABLC (D IV)

. All patients should be routinely premedicated with 50 mghydrocortisone and 10 mg chlorphenamine 15 – 30 minprior to the initial ABLC infusion (C III).

No DDRs observed following initial infusion

. If no DDRs are observed, patients should be routinelypremedicated with 50 mg hydrocortisone and 10 mg

chlorphenamine 15 – 30 min prior to the secondABLC infusion and with 10 mg chlorphenamine prior tosubsequent infusions (C III).

DDRs observed following initial or subsequent infusions

. If a DDR occurs following the initial or second infusion ofABLC, the reaction should be controlled with 50 mghydrocortisone and 50 mg pethidine (C III)

. All patients should be routinely premedicated with50 – 100 mg hydrocortisone and 10 mg chlorphenamine15 – 30 min before the second ABLC infusion (C III)

. All patients should receive premedication with 325 mgparacetamol and 10 mg chlorphenamine prior to anysubsequent ABLC infusions (C III).

3.2 Infusion ratesIt has been postulated that slowing the speed of the ABLCinfusion may also control the rate of DDRs. Several studieshave included this strategy as part of their methodology togood effect [3,24,30]. Fleming et al. [3] initially gave the ABLCinfusion over 2 h; however, the infusion time was prolonged inpatients who developed DDRs. These reactions, which weremainly chills and febrile reactions, were mild to moderate andnone were dose limiting. Similarly, Clevenbergh et al. [24]

reported that ABLC was well tolerated and fever and chillswere controlled either by premedication or by slowing thespeed of the infusion from 2 to 4 h.


. ABLC should be infused at 2.5 mg/h (B II)

. The patient should be closely monitored for any type ofDDR associated with ABLC (D IV)

. Fever and chills can be controlled by reducing the speed ofthe infusion to over 3 h (infusion rate of 1.6 mg/h) (C III).

3.3 Time of administrationThere is a paucity of published data regarding the best time toadminister ABLC infusions. Consensus opinion, however,suggests that if a patient is receiving concomitant corticoster-oids, for example for graft-versus-host disease, ABLC infu-sions should be administered shortly after the steroid dose isgiven to minimise the likelihood of DDRs and reduce theneed for steroid premedication. The consensus is that ABLCshould be administered during the day, so that if a DDR doesoccur, there will be greater number of support staff on hand toattend to the patient than at night.


. ABLC should be administered during the daytime as far aspossible in case a DDR occurs (D IV)

. If a patient is already on corticosteroids, ABLC should beadministered shortly after the steroid dose is given tominimise the likelihood of DDRs and reduce the needfor steroid premedication (D IV).



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3.4 Agitating infusion bagsConsensus opinion suggests that, in order to ensure that thedose of ABLC is constant throughout the infusion, the infusionbag should be gently agitated during the infusion, particularlyif the duration of infusion is extended to manage DDRs.


. The infusion bag should be gently agitated during theinfusion (D IV).

Based on the available data and the experience of the con-sensus panel, an algorithm on strategies to reduce the risk ofDDRs following ABLC infusions is provided in Figure 1. Thealgorithm takes into account initial premedication regimens,speed of the infusion and subsequent strategies to reduce therisk of DDRs.

4. Preserving renal function

4.1 HydrationDehydration is a major risk factor for the development ofrenal side effects when using amphotericin B and its lipid-based formulations [31]. It is important, therefore, that allpatients receiving ABLC therapy are adequately hydratedbefore and after dosing to help improve renal function.Clinical data for adults and animals suggest that adequate

hydration is important for the prevention of conventionalamphotericin B nephrotoxicity [32]. Results from a studyexamining the effects of fluid and electrolyte managementon conventional amphotericin B-induced nephrotoxicityamong extremely low birth weight infants confirm thesefindings [33]. Recent data suggest that oral rehydrationsolution is comparable to intravenous saline solution inpreventing glomerular damage, but more effective in pre-venting hypokalaemia in patients treated with conventionalamphotericin B [34].


. All patients receiving ABLC therapy should be adequatelyhydrated before and after dosing to help improve renalfunction (C III).

4.2 Monitoring renal functionClinical trials have shown that ABLC, LAB and ABCDexhibit less renal toxicity than conventional amphotericinB [7,13-15,35]. The decreased nephrotoxic potential of lipid-based formulations allows them to be used in patients withnephrotoxicity secondary to conventional amphotericin Btreatment [36]. Indeed, a recent systematic review concludedthat lipid-based formulations of amphotericin B are impor-tant in improving survival and preserving renal function incritically ill patients with systemic fungal infections [7].

DDR*

DDR*

No DDR

DDR*

No DDR

1st dose of ABLC50 mg hydrocortisone10 mg chlorphenamine2.5 mg/h infusion rate

2nd dose of ABLC50 mg hydrocortisone10 mg chlorphenamine2.5 mg/h infusion rate

*All DDRs to becontrolled with:

50 mg hydrocortisone50 mg pethidine

Subsequent dosesof ABLC

325 mg paracetamol10 mg chlorphenamine1.6 mg/h infusion rate

2nd dose of ABLC100 mg hydrocortisone10 mg chlorphenamine1.6 mg/h infusion rate

Subsequent dosesof ABLC

10 mg chlorphenamine2.5 mg/h infusion rate

Figure 1. Consensus panel algorithm on premedication and infusion rate to reduce the risk of drug delivery reactionsfollowing ABLC infusion.ABLC: Amphotericin B lipid complex; DDR: Drug delivery reaction.



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However, despite the fact that lipid-based formulations ofamphotericin B exhibit less nephrotoxicity than conventionalamphotericin B, renal side effects may still occur [37]. Anexamination of the records of 3514 patients registered inCLEAR database indicated that doubling of serum creatinineand an increase of ‡ 2.5 mg/dl occurred in 13 and 12% of thepatients receiving ABLC, respectively [37]. Therefore, closemonitoring is still of paramount importance when usinglipid-based formulations of amphotericin B, such as ABLC,in order to preserve both renal and hepatic function.Monitoring of renal function should be performed bothbefore initiating treatment and during therapy, and particu-larly close monitoring of renal function is required in patientsreceiving nephrotoxic drugs concomitantly and in patientswith pre-existing renal dysfunction.


. The patient’s renal and hepatic function should be closelymonitored (B II)

. Monitoring of renal function should be performed bothbefore initiating treatment and during therapy (B II)

. Patients receiving nephrotoxic drugs concomitantly shouldhave their renal function closely monitored (B II)

. Patients with abnormal liver function tests should be care-fully monitored and cessation of treatment considered ifliver function deteriorates (B II).

In clinical trials, various definitions of renal toxicity have beenused; however, it is generally defined as a doubling of serumcreatinine levels compared with baseline levels and/or anincrease in serum creatinine ‡ 2.5 mg/dl [3,35,37]. Availabledata suggest that serum creatinine levels may rise transientlyfollowing ABLC therapy, often stabilising after the first fewdoses (Box 1) [23,25,35]. Analysis of patients with invasivezygomycosis in the CLEAR database indicates that serum

creatinine levels remained stable during ABLC therapy (meandaily dose 4.82 mg/kg), even with concomitant use of drugsknown to be nephrotoxic [38]. Further data from CLEAR showthat in children with no previous exposure to ABLC therapy,increases in serum creatinine take place over the first week orso of therapy and then the levels stabilise [8].

Miller et al. [35] provide further evidence of the transientnature of increases in serum creatinine levels after ABLCtherapy. In this study, renal function was assessed using themedical records of adult HSCT recipients with proven orprobable invasive fungal infection. In all, 34 of the 119 patientsincluded in the study received ABLC as initial therapy. In thisgroup, there was amean percentage increase in serum creatinineat weeks 1 and 2 (~ 35 and 55%, respectively) compared withbaseline serum creatinine levels. After week 2 the serumcreatinine levels stabilised, returning to baseline levels byweek 8 [35]. Even in studies where a higher prevalence of serumcreatinine elevations were observed for ABLC compared withLAB (mean daily dose 4.3 mg/kg for both drugs), thesetreatment-induced elevations did not appear to be clinicallysignificant (no difference in withdrawal/discontinuation rates)and most patients successfully continued therapy [22].

Spikes in serum creatinine levels sometimes occur after initi-ating ABLC therapy, but these increases are usually transient. Toavoid unnecessary discontinuation of treatment, it is importantfor physicians to be aware that these changes may occur.


. Spikes in serum creatinine levels, which sometimes occurafter the first infusion of ABLC, are usually transient andmay not necessitate discontinuation of the drug (C III)

. Following ABLC infusion, all patients should have serumcreatinine levels measured daily (C III)

. Patients with abnormal serum creatinine levels should becarefully monitored and modification of treatment consid-ered if serum creatinine levels reach double the baseline levelor 200 mmol/l, whichever is higher (D IV).

5. Audit criteria

The consensus panel propose that clinical audits shouldroutinely be carried out to identify how closely local practicerelates to best practice identified in these guidelines. Theprimary objective of the audit is to identify if there is areduction in the DDR rate following premedication priorto ABLC. Secondary objectives should include assessment ofthe overall efficacy of ABLC at controlling invasive fungalinfections and renal tolerability. Recommended data to becaptured in the audit are given in Table 4.

6. Conclusion

Invasive fungal infections remain a common cause ofmorbidityand mortality in immunocompromised patients and are

Box 1. Case study: JM.

A female patient with myeloma was administered ABLC atan initial dose of 5 mg/kg/day for the treatment ofpulmonary aspergillosis. Following the initial infusion, serumcreatinine levels increased to 82 mmol/l. The patientreceived a second infusion of ABLC, but the serumcreatinine continued to rise to 125 mmol/l and by the thirdday had more than doubled (206 mmol/l). ABLC therapywas immediately discontinued and on the following day, thepatient was switched to alternative treatment. On thefourth day, at the time when the fourth dose of ABLC wasdue, the serum creatinine levels had fallen to 138 mmol/l.This reflects the transient effect of the first 3 days of ABLCtherapy on renal function, rather than a switch to alternativetreatment. This case illustrates how spikes in serumcreatinine levels, which sometimes occur after the firstinfusion of ABLC, may be transient and not necessarilyrequire discontinuation of therapy. It is important that thepatient is adequately hydrated and their renal and hepaticfunction is closely monitored.



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associated with a high cost burden. Concerns about the adverseeffects of conventional amphotericin B, in particular nephro-toxicity, has led to the development of less toxic formulations ofamphotericin B. ABLC has a broad spectrum of activity againsta wide range of fungal pathogens and has been shown to beeffective and generally well-tolerated in the treatment of pre-sumed or confirmed fungal infections in immunocompromisedpatients. The most commonly reported adverse effects aretransient DDRs, mostly fever and chills, which occur partic-ularly at the beginning of therapy and generally diminish insubsequent infusions. Clinical data suggest that fever and chillscan be adequately controlled either by premedication prior toABLC infusion or by slowing the speed of the infusion.Optimal premedicationmay include hydrocortisone and chlor-phenamine given 15 – 30 min before the infusion. Hydrocor-tisone and pethidine may be required during the infusion if aDDR occurs and does not subside within 15 – 30 min. Theinfusion should be given over 2 h, but the infusion timemay beprolonged if a patient develops a DDR All patients receivingABLC therapy should be closely monitored for any signs ofDDRs or nephrotoxicity and be adequately hydrated beforeand after dosing to help improve renal function.

7. Expert opinion

In recent years, the choice of antifungal agentsavailable to treating physicians has greatly increased. The

introduction of echinocandins and new azoles has ledto more complex fungal infection management strategiesand raised questions about the continuing role of traditionalantifungals. While it may have been believed by some thatnewer antifungals would herald the end of amphotericin Buse, the reality has proved quite different.

Due to more aggressive chemotherapeutic techniquesand an increase in the number of transplants being car-ried-out, we have seen a profound increase in the number ofseverely immunocompromised patients. Concurrently, wehave seen an evolving and broader spectrum of fungalpathogens emerging in this population. Furthermore, therehave been reports of breakthrough infections occurringwith some of the newer and more targeted agents, suchas voriconazole. Mucormycosis, for example, has becomea significant issue and can only be treated with either anamphotericin B agent or posaconazole. In light of theseemerging pathogens, there is a continuing need foramphotericin B based lipid formulations to treat suspectedor confirmed fungal infections. The exact role ofamphotericin B lipid formulations should be based onindividual circumstances and a balance between theirefficacy against a wider range of fungal infections andtheir increased toxicity compared to some of the newerantifungal agents.

Future developments in the field of amphotericin Blipid formulations will probably centre on their use incombination therapy and in combating exotic fungal infec-tions such as those by Zygomycoses and Fusarium spp.Improved diagnostic tools should also allow physiciansto maximise the appropriate use of amphotericin Blipid agents, either singly or in combination, whileminimising the exposure of patients to unnecessary toxicity.This improved targeting of therapy should lead to improvedprevention and cure rates and fewer discontinuationsof treatment.

Acknowledgements

Strategen Ltd provided editorial services to the authors andreceived fees from Cephalon Ltd in this regard.

Declaration of interest

Cephalon acted as study sponsor but were not involved inthe preparation, writing or editing of this article. Allmembers of the consensus panel detailed below attendedan advisory board and received honoraria payments fromCephalon Ltd in this regard: C Craddock, J Anson, P Chu,A Dodgson, N Duncan, C Gomez, J Mehta, S Sadullah,C Subudhi and J-L Yin.

Table 4. Data collection.

Demographic and baseline data

. Age

. Sex

. Weight

. Condition(s)

. Co-morbidities

. Chemotherapeutic history

. Neutropaenic status

. Previous antifungal therapy (including ABLC)

. Patient reaction to previous ABLC infusion

Clinical measures

. ABLC dosage and administration

. ABLC given as treatment or prophylaxis

. Premedication administered

. Immunocompetence

. DDRs: type and duration measured after each infusion

. Renal competence: serum creatinine levels before and after eachcycle of ABLC

. Response rate and duration of treatment

ABLC: Amphotericin B lipid complex; DDR: Drug delivery reaction.



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BibliographyPapers of special note have been highlighted

as either of interest (.) or of considerable

interest (..) to readers.

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AffiliationCharles Craddock†1, James Anson3, Patrick Chu3,

Andrew Dodgson2, Nick Duncan1,

Cesar Gomez4, Jayesh Mehta5, Shalal Sadullah4,

Chinari Subudhi1 & John-Liu Yin2

†Author for correspondence1Professor,

Queen Elizabeth Hospital,

Birmingham, UK

Tel: +44 (0)121 472 1311;

Fax: +44 (0)121 697 8401;

E-mail: [email protected],

Central Manchester University Hospitals,

Manchester, UK3Royal Liverpool Hospital,

Liverpool, UK4James Paget Hospital,

Great Yarmouth, UK5Professor,

Northwestern University,

Chicago, USA6Salford Royal NHS Foundation Trust,

Manchester, UK



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best practice guidelines for the management of adverse events associated with amphotericin b lipid...

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