Amphotericin-induced stridor: a review of stridor, amphotericin preparations, and their immunoregulatory effects

Amphotericin-induced stridor: a reviewof stridor, amphotericin preparations, andtheir immunoregulatory effectsMargaret M. Lowery, MD, and Paul A. Greenberger, MD

Background: Various adverse effects have been reported with the use of amphotericin B. The respiratory adverse effectsinclude dyspnea, tachypnea, bronchospasm, hemoptysis, and hypoxemia. Stridor has not been previously reported with the useof amphotericin B.Objective: To review the mechanism of action and reports of respiratory adverse effects for amphotericin B, the liposomal

preparations of amphotericin B, and the differential diagnosis of stridor.Data Sources: AMEDLINE search from 1966 to 2002 was performed to review the current literature for possible mechanisms

and immunoregulatory effects related to the infusion of amphotericin B.Results: Amphotericin B has been shown to increase tumor necrosis factor � (TNF-�) concentrations in macrophages. In

addition, it induces prostaglandin E2 synthesis and increases the production of interleukin 1� (IL-1�) in mononuclear cells. Theimmunoregulatory effects of amphotericin B include increases in apoptosis, production of monocyte chemoattractant protein 1,superoxide anion, nitric oxide, and intercellular adhesion molecule 1 expression.Conclusions: Amphotericin B induces the production of TNF-�, interferon-�, and IL-1�, which may potentiate its toxic

effects. Some liposomal preparations induced lower levels of TNF-� and nitric oxide and may be useful in patients unable totolerate amphotericin B deoxycholate.

Ann Allergy Asthma Immunol. 2003;91:460–466.

INTRODUCTIONVarious adverse effects have been reported with the use ofamphotericin B. The respiratory adverse effects include dys-pnea, tachypnea, bronchospasm, hemoptysis, and hypoxemia.Stridor has not been previously reported with the use ofamphotericin B. This study was performed to review themechanism of action and reports of respiratory adverse ef-fects for amphotericin B, the liposomal preparations of am-photericin B, and the differential diagnosis of stridor. Weperformed a MEDLINE search from 1966 to 2002 to reviewthe current literature for possible mechanisms and immuno-regulatory effects related to the infusion of amphotericin B.

CASE PRESENTATIONA 69-year-old, retired, male teacher with no past alcohol ortobacco use but with newly diagnosed acute myelogenousleukemia developed neutropenic fevers after his second in-duction of chemotherapy. His condition required treatmentwith piperacillin/tazobactam, amikacin, and vancomycin. Hiscourse was complicated by pancytopenia, line infection, andfluid overload. Because of persistent fevers, amphotericin Bwas added to his antibiotic regimen. During the initial am-

photericin B infusion of 15 mg, the patient developed pro-found dyspnea, wheezing, chills, and rigors. He also devel-oped a rash on his face, back, and chest. His oxygensaturation dropped to 90% on room air. The infusion wasdiscontinued, and the patient was treated with an albuterolnebulization, intravenous meperidine, and hydrocortisone.The patient had not received any premedications, and noother medications were infusing at the time of this reaction.For unclear reasons, the patient had not been given a 1-mgamphotericin B test dose before the full dose of amphotericinB. The Allergy/Immunology Service was consulted for am-photericin test dosing. The patient received 1 mg and then 2mg of amphotericin B without incident. Twenty minutes afterreceiving 10 mg of intravenous amphotericin B, the patientdeveloped rigors, stridor, and shortness of breath. The med-ications administered included an albuterol nebulization, in-travenous meripidine, 125 mg of methylprednisolone, di-phenhydramine, and then a racemic epinephrine nebulizationbecause of continued stridor. His symptoms resolved withthis treatment. Because of the marked respiratory distress andstridor, no further use of amphotericin B was attempted.

MEDICAL HISTORYThe patient’s medical history included chronic idiopathicthrombocytopenic purpura, nephrolithiasis, hypertension,transient ischemic attack, and depression. He was also aller-gic to radiocontrast media (rash) and naproxen sodium (an-gioedema).

Division of Allergy-Immunology, Department of Medicine, NorthwesternUniversity Feinberg School of Medicine, Chicago, Illinois.Supported by the Ernest S. Bazley Grant to Northwestern Memorial Hospitaland Northwestern University.Received for publication March 27, 2003.Accepted for publication in revised form June 10, 2003.

460 ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY

FAMILY HISTORYThe patient had a brother with unknown liver disease andpancreatic cancer. He also had a father with Parkinson disease.

PHYSICAL EXAMINATION AND LABORATORYRESULTSThe physical examination at the time of amphotericin testdosing included the following: pulse, 80/min; respirations,30/min; blood pressure, 160/80 mm Hg; and oxygen satura-tion, 90% on room air. Examination of the head, eyes, ears,nose, and throat revealed stridor but no wheezing or crackles(lungs were clear before amphotericin B test dose). Thepatient had no hives or rash. Laboratory tests revealed thefollowing: normal kidney profile except for glucose, 136mg/dL; normal liver function test results; white blood cellcount, 0.2/�L; hemoglobin, 8.5 g/dL; and platelet count,40,000/�L. A chest x-ray examination showed a small area ofatelectasis in the left lower lobe.

A DIFFERENTIAL DIAGNOSIS OF STRIDORA differential diagnosis of stridor includes the followingsteps1:I. InfectiousA. EpiglottitisB. Bacterial tracheitisC. Croup

II. CongenitalA. LaryngomalaciaB. Congenital laryngeal websC. Subglottic stenosis

III. AcquiredA. Subglottic hemangiomaB. Vocal cord paralysisC. Squamous papillomaD. Saccular cysts and laryngocelesE. Acquired laryngeal/tracheal stenosisF. Foreign bodyG. Myasthenia gravisH. AngioedemaI. Meige syndromeJ. AnaphylaxisK. Postintubation subglottic stenosis

IV. NonorganicA. Factitious stridor (Munchausen syndrome)B. Undifferentiated somatoform idiopathic anaphy-laxis

C. Vocal cord dysfunction

STRIDORStridor is a loud musical sound of constant pitch or essentiallya wheeze that signifies tracheal or laryngeal obstruction.2 Thepattern of stridor can be inspiratory, expiratory, or biphasic.With inspiratory stridor, the soft tissues at or above the levelof the vocal cord collapse with negative pressure duringinspiration.3 Expiratory stridor is produced from a decreased

diameter of the intrathoracic trachea and bronchial airwaysduring expiration.3 Biphasic stridor occurs from a fixed lesion(ie, edema at or near the cricoid cartilage) during inspirationand expiration.3 In most patients with stridor, the stridoroussound is heard on inspiration.The differential diagnosis for acute stridor includes epi-

glottitis, croup, bacterial tracheitis, acute external laryngeal/tracheal trauma or preexisting vocal cord paralysis, laryngo-malacia, subglottic stenosis with an acute viral upperrespiratory tract infection, true anaphylaxis, or a nonorganiccause of stridor. If a patient presents with stridor, a quickevaluation of the respiratory status should include observa-tion of the following: respiratory pattern, retractions, nasalflaring, cyanosis, drooling, or hoarseness. The presence ofany of these symptoms may indicate the need for emergentendoscopy and endotracheal intubation.Acute epiglottitis, or an epiglottic abscess, is a true airway

emergency that can present with stridor and be fatal, espe-cially if an abscess is not treated. In the pediatric age range,a child may have a sore throat, fever, drooling, and toxicappearance. The airway must be evaluated endoscopically.Typically, the patient is taken to the operating room, wherethe endoscope is used to evaluate the airway problem andthen an endotracheal tube is placed in the patient in a con-trolled setting. The patients are treated with intravenous an-tibiotics and extubated once the airway inflammation hasresolved. The etiologic organisms of acute epiglottitis includeHaemophilus influenza, Streptococcus pneumoniae, andgroup A �-hemolytic streptococci. Since the introduction ofthe H influenza vaccination of young children, the frequencyof episodes of acute epiglottitis has decreased significantly.Acute laryngotracheobronchitis or viral croup is common

in children from 6 months to 3 years of age.4 It is caused byparainfluenza, respiratory syncytial virus, and influenza Aand B. The child typically presents with fever, barking cough,and inspiratory stridor. Radiographs of the lateral part of theneck show subglottic narrowing; the frontal view demon-strates the classic “steeple” sign.5The usual treatment includes cool humidification, racemic

epinephrine, and steroids, usually dexamethasone. Racemicepinephrine has �-, �1-, and �2-agonist activities. The �-ag-onist induces vasoconstriction of the edematous subglotticarea, and the �2-agonist stimulates bronchial smooth musclecontraction. Steroids are given to decrease the overall inflam-matory reaction, which results in decreased airway edema.4Most children improve in a few days, but if respiratorydistress occurs, the child may require endotracheal intubation.A patient with preexisting vocal cord paralysis, laryngo-

malacia, or subglottic stenosis may develop acute stridor inassociation with a viral upper respiratory tract infection. Thepatients are treated similarly to patients with viral croup.

MECHANISMS OF ACTION AND IMMUNOLOGICEFFECTSPharmacologically, amphotericin binds to ergosterol in thefungal cell wall, which alters membrane permeability, result-

VOLUME 91, NOVEMBER, 2003 461

ing in cellular leakage and eventually cell death.6 Amphoter-icin is known to produce many adverse effects, which includefever, chills, hypokalemia, hypomagnesemia, and renal insuf-ficiency. Several in vivo and in vitro clinical studies (Table 1)have shown that amphotericin B infusion–related adversedrug reactions involve the release of IL-1� and TNF-� frommonocytes and prostaglandin E2 from monocytes and endo-thelial cells.7–9 THP-1 cells (human mononuclear cell line)stimulated with amphotericin B induced a moderate amountof IL-1� messenger RNA (mRNA) compared with the strongstimulus lipopolysaccharide.10 When THP-1 cells were com-bined with amphotericin B and calmidazolium (calmodulin-antagonistic), the amphotericin B–induced IL-1� secretionwas reduced to half that observed with THP-1 cells andamphotericin B.11 These data are consistent with calmodulin-antagonistic effects of amphotericin B. Amphotericin B hasbeen shown to produce concentration-dependent changes inintracellular calcium. Thus, it is possible that the amphoter-icin B–induced increases in ionized calcium may activatevarious enzymes, which lead to the production of IL-1�.Eriksson et al12 reported a comparison of side effects

between amphotericin B during rapid and continuous infu-sions. They found a decreased incidence of fever in 10 (25%)of 40 patients undergoing continuous 24-hour infusion vs 21(53%) of 40 patients with fever during 4-hour rapid infusionsof amphotericin B. The incidence of chills and rigors alsodecreased with continuous vs rapid infusions: 5 (13%) vs 21(53%), respectively.12 Furthermore, they documented an in-crease in C-reactive protein with the rapid infusion group at24 and 48 hours after the initiation of treatment with ampho-tericin B.12

FORMULATIONS OF AMPHOTERICINAmphotericin B is available in 3 categories of lipid formu-lation, which include amphotericin B lipid complex (Abelcet;Elan Biopharmaceuticals, San Diego, CA), amphotericin Bcholesteryl sulfate complex (Amphotec; InterMune Inc, Bris-bane, CA), and liposomal amphotericin B (Ambisome; Fuji-sawa, Deerfield, IL). These lipid formulations may be en-gulfed by macrophages, which then release freeamphotericin.13 In vivo amphotericin B binds to low-densitylipoprotein receptors and is internalized into the cell.13 Themore stable amphotericin B lipid carrier complex allows asmaller amount of amphotericin B bound to low-densitylipoprotein, thus resulting in lower toxicity.13 All of the lipid

formulations have an overall lower incidence of adverseeffects, most notably lower nephrotoxicity.

ADVERSE EFFECTS OF AMPHOTERICINIn a patient in whom liver transplantation failed, rising con-centrations of amphotericin B were accompanied by drugdeposition in the lung.14 The patient was given liposomalamphotericin B, 150 mg (2.2 mg/kg), and on day 5, theamphotericin level peaked at 33.6 mg/L.14 On autopsy, theconcentration of amphotericin B was 69.4 �g/g in the lungsand 105.6 �g/g in the liver.14 In the patients without liverdysfunction who were treated with Ambisome (n � 6), themedian liver-lung ratio was 15:1, whereas in this patient, itwas 1.5:1.14 The authors hypothesized that the failure of theliver reticuloendothelial system (RES) resulted in inadequateclearance of Ambisome with drug accumulation in thelungs.14 Thus, an adequately functioning RES seems impor-tant in the metabolism for the lipid formulations of ampho-tericin B. Liver function tests should be evaluated beforeinitiating amphotericin B, since, in patients with hepaticinsufficiency, there may be accumulation of amphotericin B.Anaphylaxis has been reported with liposomal prepara-

tions.15 Stridor has not been previously reported with ampho-tericin B infusions. On the other hand, several case reports ofbronchospasm, hypoxemia, and acute pulmonary infiltrateshave been reported with amphotericin B infusions.15–19,21–27Reports of acute dyspnea and shortness of breath have beenreported with both amphotericin B and liposomal amphoter-icin.15–19,21–26 Schneider et al16 reported a fatal allergic reaction(hypotension, dyspnea, bronchospasm, and asystole) to Am-bisome; subsequently, the patient died of cerebral edemawithin 36 hours of the allergic reaction. Rolland et al17described a 73-year-old woman receiving amphotericin B onday 4 who developed respiratory distress, bronchospasm,cyanosis, and hypoxia with an oxygen saturation of 88% on2-L nasal cannula. Another patient received amphotericin Bdeoxycholate, which was tolerated except for some renalinsufficiency.18 He was converted to amphotericin B lipidcomplex and, 90 minutes into the infusion, complained ofdyspnea and chills; he developed severe hypoxemia with aPO2 of 49 mm Hg and an oxygen saturation of 80%.18 Kauff-man and Wiseman19 described a 33-year-old man with Coc-cidioides immitis meningitis. He initially was treated withintraventricular amphotericin B, which was associated withrigors, fever, and vomiting. He developed renal insufficiency

Table 1. Proposed Mechanisms of Toxicity of Amphotericin B

Associated reactants Target cell Mechanism of action of amphotericin B Reference(s)

Prostaglandin E2 Mononuclear cell Inducer of prostaglandin E2 synthesis 8TNF-� Macrophages Increase TNF-� levels

Increase INF-� mRNA9,31,42

IL-1� Mononuclear cells Increase IL-1� mRNA 10Increase IL-1� secretion

Abbreviations: IL-1�, interleukin 1�; mRNA, messenger RNA; TNF-�, tumor necrosis factor �.


and was switched to Abelcet lipid complex (Elan Biophar-maceuticals). After 6 weeks, he was switched to Amphoteccholesteryl sulfate complex (InterMune Inc) because of per-sistent renal insufficiency. Within 1 hour of the Amphotecinfusion, the patient developed lip swelling and dyspnea.19Torre et al20 reported anaphylaxis with Ambisome. A 10-year-old girl with Crohn disease developed a nosocomialinfection with Candida albicans in the urine and bronchialaspirate after intestinal resection and colostomy surgery com-plicated by acute respiratory distress syndrome.20 She wastreated with Ambisome and on day 4 had diffuse erythemawith the infusion. On day 5, she developed flushing, diffuseerythema, hypertension, and bronchospasm with desaturationto 84%.20In a study of 837 patients with neutropenia and fever,

liposomal amphotericin B (3-mg/kg) infusions resulted in“anaphylactic reactions” in 7 (1.7%) of 422 patients.21 Flush-ing occurred in 46 (10.9%) of these patients, whereas withvoriconazole (a second-generation triazole), flushing was re-ported in 14 (3.4%) of 415 patients.21 Stridor was not reportedseparately but could have been part of the anaphylactic reac-tions. Curiously, transient visual changes were much morecommon with voriconazole, with 91 (21.9%) of 415 patientscompared with 3 (0.7%) of 22 patients receiving liposomalamphotericin B.21 None of the aforementioned reports ofrespiratory distress or anaphylaxis used amphotericin B skintesting or drug-specific IgE antibody testing.

IMMUNOREGULATORY EFFECTS OFAMPHOTERICINReview of the literature reveals several reports of lethalpulmonary reactions associated with amphotericin B andleukocyte transfusions. Wright et al22 reviewed retrospectivecase reports of patients given leukocyte transfusions andamphotericin B. They found that 14 (64%) of 22 patients hadrespiratory deteriorations that included sudden dyspnea, hypox-emia, hemoptysis, and interstitial infiltrates on chest radio-graph.22 The patients in this study had documented bacterialinfections, and three quarters of the patients had gram-negativebacteria septicemia. Therefore, it is possible that endotoxin in-duction of IL-1 and TNF-�, in addition to amphotericin-inducedIL-1 and TNF-� production, may have contributed to the pul-monary toxicity. This study also reported diffuse intra-alveolarhemorrhage in 4 patients apparent on lung biopsy specimens orat autopsy.22 Berliner et al28 reported that Zymosan activatedplasma and amphotericin B induced pulmonary leukostasis inrabbits. They concluded that amphotericin B causes aggregationof polymorphonuclear leukocytes (PMNs) and may result inendothelial cell damage in the lungs of humans.28Hardie et al29 reported amphotericin B–treated sheep had

increased resistance to airflow, lung lymph thromboxane B2levels, 6-keto prostaglandin F1� concentrations, and a widen-ing of the arteriolar-alveolar oxygenation gradient. Ibuprofenpretreatment before amphotericin B infusions delayed andblunted the rise in transpulmonary airflow, decreased (A-a)

oxygen, attenuated the rise in pulmonary artery pressure, anddecreased thromboxane B2 levels.29 Hardie et al concludedthat the elevated concentrations of prostaglandins induced byamphotericin B infusions may cause bronchoconstriction or in-creased vascular permeability changes, resulting in hypoxemia.TNF-� is thought to mediate endotoxic shock and inflam-

mation in humans and animals.30 In a study by Chia andPollack,9 amphotericin B–stimulated murine macrophagesproduced TNF in a dose-dependent manner. Another in vitrostudy by Vonk et al31 showed increased TNF-� and TNF-�mRNA with amphotericin B–stimulated PBMCs. WhenTHP-1 cells were stimulated with amphotericin B, TNF-�levels peaked at 2 hours.10 This effect might be analogous tothe 60- to 180-minute period when adverse drug reactionsoccur with an amphotericin B infusion.10 Thus, TNF-� mayinduce inflammation in the trachea, subglottic area, and bron-chial tree, which may manifest as stridor or bronchoconstric-tion in a patient experiencing a reaction to amphotericin B.Gigliotti et al8 reported that amphotericin B was a potent

inducer of prostaglandin E2 synthesis in human and murinemononuclear cells. When ibuprofen was administered 30minutes before amphotericin B, the incidence of severe chill-ing reactions was reduced from 69% to 15%.8 Ibuprofen is aprostaglandin inhibitor and in theory may have prevented theprostaglandin E2 induction by amphotericin B.Several studies have found that amphotericin B has various

immunoregulatory effects (Table 2). IL-1 receptor agonist(IL-1Ra) is the natural antagonist of IL-1�. Rogers et al10reported that amphotericin B–stimulated THP-1 cells pro-duced large amounts of IL-1Ra in a dose- and time-dependentmanner. Further analysis revealed that amphotericin B in-duced soluble IL-1Ra mRNA.10 Because IL1-Ra is a compet-itive inhibitor of IL-1�, the amphotericin B induction ofIL-1Ra may reduce the IL-1� toxicity in some patients, ifthese findings can be extrapolated to humans. In addition,Rogers et al32 determined that amphotericin B increased themRNA and concentrations of IL-8, monocyte chemoattrac-tant protein 1, macrophage inflammatory protein 1�, inter-cellular adhesion molecule 1, and the mRNA of CD44 in thehuman monocytic cell line THP-1. The effect on neutrophilsincludes inhibition of chemotaxis and chemiluminescence,decreased binding of chemotactic receptors, and increasedadherence of PMNs.33–35 Using macrophages, amphotericinhas been shown to increase phagocytic function, inhibitgrowth of microorganisms, decrease cell viability, increaseapoptosis, and increase tumoricidal activity.36–38 Furthermore,macrophage and granulocyte stem cell production increasedin the presence of amphotericin.38 Lin et al38 reported an8-fold increase in the number of colony-forming units in cellculture 4 days after intraperitoneal injection into mice and a3-fold increase in the number of colony-forming units in thespleen at day 7. The combination of inflammatory mediators,chemoattractants, and adhesion molecules result in the aggre-gation of PMNs. At the site of tissue localization, various


cytokines, chemokines, and products of oxidative metabolismare released, which may contribute to the toxic effect ofamphotericin B.Nitric oxide and TNF-� production were reduced when

amphotericin B was presented as a lipid formulation in vitrofrom lipopolysaccharide-stimulated murine peritoneal macro-phages.39–42 Amphotec (cholesteryl sulfate complex) and am-photericin B lipid complex (small-sized complexes) showed75% and 50% reductions, respectively, in nitric oxide,whereas Ambisome (liposome) and the large Abelcet com-plexes showed 92% and 93% reductions, respectively, innitric oxide at an amphotericin B concentration of 1 �g/mL.42The TNF-� production was reduced by 91% with Ambisomeand by 93% with Abelcet, whereas Amphotec and amphoter-icin B lipid complexes had reductions in TNF-� of 73% and43%, respectively, at an amphotericin concentration of 1�g/mL.42 Another study43 reported that liposome-inhibitedlipopolysaccharide induced TNF secretion at a posttranscrip-tional level. Therefore, it is likely that the liposomal formu-lation of amphotericin B with decreased production of TNF-�and nitric oxide may have less toxicity. If amphotericin B isinternalized into the macrophage, then the slower release ofamphotericin B may modify its immunostimulatory effectsand reduce its toxicity.

DESENSITIZATION AND RECOMMENDATIONSThere is emerging evidence for satisfactory effectiveness ofitraconazole or voriconazole instead of amphotericin B.21 Ifno adequate alternative to amphotericin B is available, onecan proceed with desensitization in an intensive care unitsetting. Before proceeding with desensitization, the benefitsand risks of this treatment must be understood by the patientor responsible adult. If a patient has an anaphylactic reactionto amphotericin B but requires amphotericin B for treatmentof a systemic fungal infection, desensitization would be con-sidered and has been described previously. The initial dose ofamphotericin B was a 10–6 dilution administered during 10minutes intravenously. Subsequently, increasing 10-fold di-lutions were administered during 10 minutes until a 10–1dilution containing a dose of 1 mg was infused in more than30 minutes. Then, 30 mg in 250 mL of dextrose (5%) wasinfused for 4 hours.In summary, amphotericin B has been shown to induce

production of TNF-�, interferon-�, and IL-1�, which couldpotentiate its toxic effects. Lipid formulations of amphoteri-cin B have been associated with a lower incidence of adverseeffects, especially nephrotoxicity. The liposomal prepara-tions, in particular, Ambisome and Abelcet, induced lowerlevels of TNF-� and nitric oxide. The lipid formulations are

Table 2. Immunoregulatory Effects of Amphotericin B

Cell type Action of amphotericin B System Reference(s)

PMN Inhibition or decrease of chemotaxis Human PMNs 33–35Inhibition of chemiluminescence Human PMNs 33Decrease binding of chemotactic receptors Human PMNs 34,35

Macrophage Increase tumoricidal activity Murine fibrosarcoma cells 37Increase cytotoxic effect of IFN-� and

amphotericin B37

Increased phagocytic function Mice peritoneal macrophages 38Inhibit growth of Listeria monocytogenes 38Increase in macrophage-granulocyte stem cells

in spleen and bone marrow38

Increase superoxide anion release after challengewith Haemophilus capsulatum and zymosanand in combination with IFN-�

Murine peritoneal macrophages 41

Increase in superoxide anion after stimulationwith phorbol myristate acetate

Human monocyte-derivedmacrophages

44

Increase Ia antigens 44Increased nitric oxide synthesis Murine macrophage-like J774.16

cells39

PBMC Decreased cell viability and increased apoptosis Human PMBCs 36Increased IL-8 and IL-8 mRNA 36Increased MCP-1 and MCP-1 mRNA Human monocytic THP-1 cell line 32Increased MIP-1� and MIP-1� mRNA 32Increased ICAM-1 and ICAM-1 mRNA 32Increased CD44 mRNA 32Increase IL1-Ra and soluble IL1-Ra Human monocytic THP-1 cell line 10

Abbreviations: ICAM-1, intercellular adhesion molecule 1; IFN-�, interferon �; IL-8, interleukin 8; IL1-Ra, interleukin 1 receptor agonist; MCP-1,monocyte chemoattractant protein 1; MIP-1�, macrophage inflammatory protein 1�; mRNA, messenger RNA; PBMC, peripheral blood mono-nuclear cell; PMN, polymorphonuclear leukocytes.


expensive and do not necessarily reduce the incidence ofrigors. If a patient has not received amphotericin B before,then a careful test dose (1 mg for 30–60 minutes followed by30–60 minutes of observation) is followed by the regulardose (0.5–1.0 mg/kg for 4–6 hours). If chills and rigorsoccur, premedication can include acetaminophen, 650 mgorally, diphenhydramine, 25 to 50 mg orally, and meperidine,25 mg intravenously. The latter can be repeated once orsubstituted with hydromorphone hydrochloride, 0.5 mg intra-venously. In the event of persistent rigors or anaphylactoidreaction, a lipid formulation of Ambisome can be substituted,but the patient must be monitored for the development of anadverse reaction (eg, bronchoconstriction and anaphylaxis).

REFERENCES1. O’Hollaren MT, Everts EC. Evaluating the patient with stridor.Ann Allergy. 1991;67:301–305.

2. Hollingsworth HM. Wheezing and stridor. Clin Chest Med.1987;8:231–240.

3. Cohen LF. Stridor and upper airway obstruction in children.Pediatr Rev. 2000;21:4–5.

4. Cressman WR, Myer CM III. Diagnosis and management ofcroup and epiglottitis. Pediatr Clin North Am. 1994;41:265–276.

5. Goodman TR, McHugh K. The role of radiology in the evalu-ation of stridor. Arch Dis Childhood. 1999;81:456–459.

6. Patel R. Antifungal agents, part I: amphotericin B preparationsand flucytosine. Mayo Clin Proc. 1998;73:1205–1225.

7. Cleary JD, Chapman SW, Nolan RL. Pharmacologic modula-tion of interleukin-1 expression by amphotericin B-stimulatedhuman mononuclear cells. Antimicrob Agents Chemother. 1992;36:977–981.

8. Gigliotti F, Shenep JL, Lott L, Thornton D. Induction of pros-taglandin synthesis as the mechanism responsible for the chillsand fever produced by infusing amphotericin B. J Infect Dis.1987;156:784–789.

9. Chia JK, Pollack M. Amphotericin B induces tumor necrosisfactor production by murine macrophages. J Infect Dis. 1989;159:113–116.

10. Rogers PD, Jenkins JK, Chapman SW, et al. Amphotericin Bactivation of human genes encoding for cytokines. J Infect Dis.1998;178:1726–1733.

11. Rogers PD, Kramer RE, Chapman SW, Cleary JD. Amphoter-icin B-induced interleukin-1� expression in human monocyticcells is calcium and calmodulin dependent. J Infect Dis. 1999;180:1259–1266.

12. Eriksson U, Seifert B, Schaffner A. Comparison of effects ofamphotericin B deoxycholate infused over 4 or 24 hours: ran-domized controlled trial. BMJ. 2001;322:579–582.

13. Hartsel S, Bolard J. Amphotericin B: new life for an old drug.Trends Pharmacol Sci. 1996;17:445–459.

14. Heinemann V, Bosse D, Jehn U, et al. Enhanced pulmonaryaccumulation of liposomal amphotericin B (Ambisome) in acuteliver transplant failure. J Antimicrob Chemother. 1997;40:295–297.

15. Laing RB, Milne LJ, Leen CL, et al. Anaphylactic reactions toliposomal amphotericin. Lancet North Am Ed. 1994;344:682.

16. Schneider P, Klein RM, Dietze L, et al. Anaphylactic reaction toliposomal amphotericin (Ambisome). Br J Haematol. 1998;102:1108–1109.

17. Rolland WA, Guharoy R, Ramirez L, et al. Respiratory distresssecondary to both amphotericin B deoxycholate and lipid com-plex formulation. Vet Hum Toxicol. 2000;42:222–223.

18. Garnacho-Montero J, Ortiz-Leyba C, Garcia Garmendia JL,Jimenez Jimenez FJ. Life-threatening adverse event after am-photericin B lipid complex treatment in a patient treated previ-ously with amphotericin B deoxycholate. Clin Infect Dis. 1998;26:1016.

19. Kauffman CA, Wiseman SW. Anaphylaxis upon switching lip-id-containing amphotericin B formulations. Clin Infect Dis.1998;26:1237–1238.

20. Torre I, Lopez-Herce J, Vazquez P. Anaphylactic reaction toliposomal amphotericin B in children. Ann Pharmacother.1996;30:1036–1037.

21. Walsh TJ, Pappas P, Winston DJ, et al. Voriconazole comparedwith liposomal amphotericin B for empirical antifungal therapyin patients with neutropenia and persistent fever. N Engl J Med.2002;346:225–233.

22. Wright DG, Robichaud KJ, Pizzo PA, Deisseroth AB. Lethalpulmonary reactions associated with the combined use of Am-photericin B and leukocyte transfusions. N Engl J Med. 1981;304:1185–1189.

23. Haber RH, Oddone EZ, Gurbel PA, Stead WW. Acute pulmo-nary decompensation due to amphotericin B in the absence ofgranulocyte transfusion. N Engl J Med. 1986;315:836.

24. Ringden O, Andstrom E, Remberger M, et al. Allergic reactionsand other rare side-effects of liposomal Amphotericin. LancetNorth Am Ed. 1994;344:1156–1157.

25. Bishara J, Weinberger M, Lin AY, Pitlik S. AmphotericinB—not so terrible. Ann Pharmacother. 2001;35:308–309.

26. Johnson MD, Drew RH, Perfect JR. Chest discomfort associ-ated with liposomal amphotericin B: report of three cases andreview of the literature. Pharmacotherapy. 1998;18:1053–1061.

27. Johnson JR, Kangas PJ, West M. Serious adverse event afterunrecognized substitution of one amphotericin B lipid prepara-tion for another. Clin Infect Dis. 1998;27:1342–1343.

28. Berliner S, Weinberger M, Ben-Bassat M, et al. Amphotericin Bcauses aggregation of neutrophils and enhances pulmonary leu-kostasis. Am Rev Respir Dis. 1985;132:602–605.

29. Hardie WD, Wheeler AP, Wright PW, et al. Effect of cycloox-ygenase inhibition on amphotericin B-induced lung injury inawake sheep. J Infect Dis. 1992;166:134–138.

30. Tracey KJ, Fong Y, Hesse DG, et al. Anti-cachectin/TNF mono-clonal antibodies prevent septic shock during lethal bacterae-mia. Nature. 1987;330:662–664.

31. Vonk AG, Netea MG, Denecker NE, et al. Modulation of thepro- and anti-inflammatory cytokine balance by amphotericinB. J Antimicrob Chemother. 1998;42:469–474.

32. Rogers PD, Stiles JK, Chapman SW, Cleary JD. AmphotericinB induces expression of genes encoding chemokines and celladhesion molecules in the human monocytic cell line THP-1.J Infect Dis. 2000;182:1280–1283.

33. Bjorksten B, Ray C, Quie PG. Inhibition of human neutrophilchemotaxis and chemiluminescence by amphotericin B. InfectImmunity. 1976;14:315–317.

34. Yasui K, Masuda M, Matsuoka T, et al. Miconazole and am-photericin B alter polymorphonuclear leukocyte functions andmembrane fluidity in similar fashions. Antimicrob Agents Che-mother. 1988;32:1864–1868.

35. Lohr KM, Snyderman R. Amphotericin B alters the affinity andfunctional activity of the oligopeptide chemotactic factor recep-


tor on human polymorphonuclear leukocytes. J Immunol. 1982;129:1594–1599.

36. Reyes E, Cardona J, Prieto A, et al. Liposomal amphotericin Band amphotericin B-deoxycholate show different immunoregu-latory effects on human peripheral blood mononuclear cells.J Infect Dis. 2000;181:2003–2010.

37. Perfect JR, Granger DL, Durack DT. Effects of antifungalagents and � interferon on macrophage cytotoxicity for fungiand tumor Cells. J Infect Dis. 1987;156:316–323.

38. Lin H, Medoff G, Kobayashi GS. Effects of amphotericin B onmacrophages and their precursor cells. Antimicrob Agents Che-mother. 1977;11:154–160.

39. Mozaffarian N, Berman JW, Casadevall A. Enhancement ofnitric oxide synthesis by macrophages represents an additionalmechanism of action for amphotericin B. Antimicrob AgentsChemother. 1997;41:1825–1829.

40. Stuehr DJ, Marletta MA. Induction of nitrate/nitrate synthesis inmurine macrophages by BCG infection, lymphokines, or inter-feron-�. J Immunol. 1987;139:518–525.

41. Wolf JE, Massof, SE. In vivo activation of macrophage oxida-tive burst activity by cytokines and amphotericin B. InfectImmunity. 1990;58:1296–1300.

42. Larabi M, Legrand P, Appel M, et al. Reduction of NO synthaseexpression and tumor necrosis factor alpha production in mac-rophages by amphotericin B lipid carriers. Antimicrob AgentsChemother. 2001;45:553–562.

43. Brisseau GF, Kresta A, Schouten D, et al. Unilamellar lipo-somes modulate secretion of tumor necrosis factor by lipopo-lysaccharide-stimulated macrophages. Antimicrob Agents Che-mother. 1994;38:2671–2675.

44. Wilson E, Thorson L, Speert DP. Enhancement of macrophagesuperoxide anion production by amphotericin B. AntimicrobAgents Chemother. 1991;35:796–800.

Requests for reprints should be addressed to:Paul A. Greenberger, MDDivision of Allergy-Immunology676 N Clair StSuite 14018Chicago, IL 60611E-mail: [email protected]


Documents

Amphotericin-induced stridor: a review of stridor, amphotericin preparations, and their immunoregulatory effects