P&T News: June 2001

Treatment of Invasive Aspergillosis

Dena M. Behm Dillon, Pharm.D. and Linda M. Schrand, Pharm.D.
Peer Review Status: Internally Peer Reviewed by Rachel Miller, M.D., Associate Professor, division of Infectious Diseases, Department of Internal Medicine

Conventional Amphotericin B
For over 40 years, amphotericin B has been the standard treatment for IA, particularly for severe and life-threatening infections.² While amphotericin B is associated with a number of adverse reactions, in many cases the efficacy of the drug outweighs the risks.

Mechanism of Action
Amphotericin B exerts its antifungal effect by binding to ergosterol (similar to cholesterol) in the fungal cell wall, disrupting cell wall integrity, and thus increasing the membrane permeability. This process leads to cell lysis and the loss of intracellular contents necessary for cell survival.³

Efficacy
The overall response rate for IA reported with amphotericin B has been 37% (range 14% to 83%). The wide response range can be accounted for by wide variation in the reported patient populations with respect to underlying diseases, extent of infection, resolution of neutropenia or other immunodeficiency, and duration of follow-up.²

Adverse Effects
Amphotericin B use, however, is complicated by infusion-related reactions, renal toxicity, and related electrolyte disturbances.

• Infusion Reactions
  Infusion-related reactions include fever, chills, rigors, nausea, and vomiting, which can be reduced through the use of premedications or by slowing the infusion rate.⁴ The standard premedications used at UIHC include diphenhydramine (25 to 50 mg PO or IV) and/or acetaminophen (325 to 650 mg PO), administered 30 to 60 minutes prior to each dose of amphotericin B. Meperidine (25 to 50 mg IV) can be given during the infusion to relieve fever and chills. Premedicating with intravenous hydrocortisone (25 mg) can also be considered for patients who have had severe fever and chills with prior doses.⁴
• Nephrotoxicity
  Although an increase in serum creatinine is common, drug administration can be maintained as long as the degree of nephrotoxicity remains moderate (SCr <2.5 mg/dL or glomerular filtration rate falls no more than 40% from baseline).³ If renal dysfunction becomes more severe, the dose may be reduced by administering the drug every other day or in an interrupted fashion (e.g., every two to five days), if clinical condition will allow.³

  The mechanism of renal toxicity is not entirely clear. Unfortunately, amphotericin B does have a weak affinity for the cholesterol molecules found in mammalian cell membranes. This results in the formation of intramembranous pores that alter the cell membrane permeability. In the kidney, this may cause direct renal tubular damage.³ Another hypothesis is that amphotericin B may affect tubuloglomerular feedback resulting in a functional reduction in glomerular filtration that is unrelated to structural damage to the renal tubule cells.³ This can lead to increased serum creatinine and urea concentrations, a lessened ability to concentrate urine, hypokalemia, magnesium-wasting, or renal tubular acidosis.³

• Electrolyte Wasting (Potassium and Magnesium)
  The increased membrane permeability and other lesser defined mechanisms also lead to the wasting of other electrolytes.³ Hypokalemia and hypomagnesemia are common during amphotericin B therapy. These abnormalities may contribute to a lessened ability to concentrate the urine. If deficits in both electrolytes occur, the hypokalemia may be resistant to potassium replacement therapy unless the hypomagnesemia is corrected first.³ Amiloride 5 mg twice daily has also been used to prevent the development of hypokalemia and may also reduce urinary magnesium losses.⁶

Strategies to Minimize Nephrotoxicity

• Sodium Loading
  Amphotericin's effect on glomerular filtration rate (GFR) is enhanced by sodium depletion and reduced by sodium loading. Therefore, it is important to maintain sodium balance during amphotericin B therapy. The most common method for reducing the risk of nephrotoxicity is to maintain sodium balance in all patients through the administration of 500 to 1000 ml of 0.9% sodium chloride before and/or after the amphotericin B infusion to prevent hyponatremia if the patient's fluid status allows.^{3, 4} Another method that can be used is the administration of a high sodium content antibiotic (e.g., penicillin class), if such concomitant antimicrobial therapy is indicated.^3,4 Salt-restricted diets and drugs that potentiate salt loss (e.g., diuretics) should be avoided.⁴ In addition, patients should be evaluated for overt sodium depletion and, if found, it should be corrected by administering 150 mEq sodium (e.g., approximately 2 teaspoons salt), in addition to normal or liberalized dietary intake in patients who are not at risk for volume overload (e.g., patients with cardiac failure, cirrhosis patients with ascites, or patients with renal failure).^3-5
• Discontinue Diuretic Therapy
  Because diuretic therapy can cause intravascular volume depletion as well as sodium wasting, the use of diuretics should be avoided, if possible. One small study of 113 patients being treated with amphotericin B demonstrated that patients who received diuretics during their therapy experienced a 12.5-fold increase in nephrotoxicity.⁷
• Avoid Concomitant Nephrotoxic Drugs
  Synergistic toxicity is generally thought to occur when concomitant nephrotoxic drugs (e.g., aminoglycosides, radiocontrast agents, cisplatin, etc.) are used.
• Continuous Infusion
  A recently published study demonstrated that administering amphotericin B as a continuous infusion (along with the sodium load) reduces nephrotoxicity and lowers infusion-related adverse effects (e.g., fever, chills, rigors).⁸ In this unblinded study, the amphotericin B was given in 500 ml of 5% dextrose without any additives and administered through a separate line either over 24 hours as a continuous infusion (n=40) or over 4 hours as a rapid infusion (n=40). The continuous infusion arm trended toward higher daily and cumulative doses. There were significantly more dose reductions and infusion-related reactions (fever, chills, vomiting) in the arm receiving the rapid infusion as compared to the continuous infusion. The ratio of peak serum creatinine to baseline creatinine concentrations was also significantly higher in the rapid infusion group as compared to the continuous infusion, but returned to normal in all but two patients within three months after completion of therapy. The continuous infusion was found to be at least as effective as rapid infusion as it related to mortality; more deaths occurred in the rapid infusion arm as compared the continuous infusion (3 versus 0, respectively).
• Total Doses Less Than 4 grams
  Renal impairment following cumulative doses less than 4 grams is usually reversible.³

Dosing
IA should be treated with the highest recommended dose (1 to 1.5 mg/kg/day) of amphotericin B.²

Lipid-Based Formulations of Amphotericin B
The lipid-based formulations [i.e., amphotericin B lipid complex (ABLC; Abelcet®, Liposome Company), amphotericin B colloidal dispersion (ABCD, Amphotec®, Sequus Pharmaceuticals), and liposomal amphotericin B (L-AMB, AmBisome®, Fujisawa)] have not demonstrated superior efficacy in the treatment of IA. The main advantage to their use is related to an attenuation of nephrotoxicity. They are currently indicated for patients who are refractory to or intolerant of conventional amphotericin B. Although these formulations are not free of nephrotoxic adverse effects, the lipid-based formulation allows a larger dose to be administered over a longer period of time with relatively less renal toxicity.⁹ The lipid-based formulations differ in the type of phospholipid adjunct, as well as the phospholipid:amphotericin B ratio.¹⁰ There are no head-to-head comparisons of the lipid-based formulations; therefore, it is unknown if one agent offers any significant therapeutic advantage over another. ABLC was the first lipid formulation to be marketed, has the most information on pediatric use, and is the least expensive. ABLC is the lipid-based product on Formulary at UIHC; its use is restricted to Pharmacy and Therapeutics Subcommittee-approved indications which include patients who have a documented systemic fungal infection, have demonstrated either refractoriness or intolerance to amphotericin B, and are not candidates to receive other appropriate antifungals. The remainder of the discussion for this section will focus on the available literature for ABLC.

Mechanism of Action
ABLC consists of lipid bilayers, called ribbons, carrying 33 mol % concentration of amphotericin B. It is thought that the lipid complex releases the active amphotericin at the specific site of the fungal infection through the action of phospholipases (released from the vascular smooth muscle, macrophages, and the infecting fungi). The active amphotericin then binds to the ergosterol in the fungal cell wall. This target-specific action is thought to reduce the risk of nephrotoxicity through reduced uptake into human cells.¹⁰

Efficacy
Most of the studies of ABLC have been compassionate use or case series studies in which small numbers of patients received the drug as second-line therapy after either becoming intolerant of or failing therapy with conventional amphotericin B. A summary of the studies evaluating the use of ABLC in the setting of IA is presented in Table 1.^11-15

Adverse Effects
The most common adverse effects with ABLC are infusion-related reactions (e.g., chills, fever, nausea, vomiting, and hypotension). The incidence is similar to that seen with conventional amphotericin B.^{12, 17} The same pre-medications described above for conventional amphotericin B are used for ABLC infusion-related reactions. Although the incidence of nephrotoxicity is lower than seen with conventional amphotericin B, an 11% incidence of increased serum creatinine is reported in the package insert¹⁶ and higher rates have been described in the individual studies^11,12 (see Table 1). In order to prevent possible nephrotoxicity, it is prudent to minimize risks in ways similar to the methods listed above for conventional amphotericin B. It is common practice at the UIHC to provide sodium loading for patients receiving ABLC, if the patient's fluid status allows. However, none of the current literature addresses this practice. Electrolyte wasting can also occur with ABLC. One study¹⁷ comparing conventional amphotericin B to ABLC found a similar incidence of hypokalemia and hypomagnesemia between the two treatments.

Dosing
The recommended dose of ABLC is 5 mg/kg/day administered at a rate of 2.5 mg/kg/hour.¹⁶ If the infusion time exceeds 2 hours, the infusion bag must be shaken every 2 hours to mix the contents.

Itraconazole
Due to the high incidence of intolerance to amphotericin B and the lack of alternative therapies for invasive aspergillosis, the introduction of itraconazole in 1992 sparked much interest. Itraconazole, a synthetic broad-spectrum triazole, is currently available as an injection, oral solution, and capsule. The intravenous (IV) and oral formulations are used for the treatment of aspergillosis in patients who are intolerant of or who are refractory to amphotericin B therapy.

Mechanism of Action
Itraconazole inhibits the cytochrome P450-dependent synthesis of ergosterol, which is a vital component of fungal cell membranes.^18-20 This inhibition is also partially responsible for the drug interactions encountered with itraconazole.

Efficacy
A multicenter open study was conducted by the Mycoses Study Group to determine the efficacy of oral itraconazole for invasive aspergillosis.²¹ Patients were given 200 mg three times daily for 4 days, then 200 mg twice daily. The overall response rate at the end of treatment was 39% (30/76). This response rate appears relatively low. However, the authors commented that many of the patients were very ill, including patients who were neutropenic or had undergone bone marrow transplants. They noted that 22% of patients in this study failed therapy, compared with 45% of similar patients treated with amphotericin B. Unfortunately, to date there have been no studies directly comparing itraconazole to amphotericin B for the treatment of aspergillosis, so the comparison is only based on historical data.

Based on this study, a comparative trial was attempted by the Mycoses Study Group and the manufacturer of itraconazole; however, it could not be completed due to enrollment reasons. Therefore, an analysis was conducted using the unpublished data from the remaining 125 patients who had received oral itraconazole through the compassionate use studies and who met the criteria for invasive aspergillosis by the Mycoses Study Group criteria.²² The overall response rate was 63% (79/125). One possible explanation for the better response rate in this analysis over the previous study is that fewer patients had extrapulmonary disease.

There have been no published trials that study the use of IV itraconazole for the treatment of disseminated aspergillosis. The evidence for efficacy of IV itraconazole is limited to animal data. When given either orally or parenterally to normal and immunosuppressed guinea pigs with disseminated aspergillosis, itraconazole increased survival rates and sterilized organ systems as compared to placebo-treated animals.²⁰

The only published clinical trial using IV itraconazole for the treatment of aspergillosis is limited to pulmonary aspergillosis. This small study's objective was to evaluate the effects of itraconazole as first line therapy for pulmonary aspergillosis in heart transplant recipients. All four patients who initially received IV itraconazole were switched to amphotericin B because of radiographic and/or clinical worsening of the infection. All three patients who initially received amphotericin B had improvement of infection. The authors concluded that in heart transplant recipients, amphotericin B was superior to itraconazole in the treatment of invasive pulmonary aspergillosis.²³

Adverse Effects
Common adverse effects observed with itraconazole include nausea, vomiting, hypokalemia, elevated liver function tests, and rash. Liver function tests should be monitored in patients with preexisting hepatic function abnormalities and assessed for the development of any sign or symptom suggestive of liver dysfunction. Unfortunately, safety with the use of itraconazole beyond 14 days has not yet been established.²⁰ When itraconazole was administered IV to dogs and healthy human volunteers, negative inotropic effects were seen.^{18- 20} If signs or symptoms of congestive heart failure occur during itraconazole administration, its continued use should be reassessed.²⁰

Dose/Administration
The dose for the oral formulations is 200 mg three times daily for 3 to 4 days and then twice daily when used for aspergillosis.^18,19,24 The IV formulation is dosed 200 mg twice daily for the first 2 days of therapy and 200 mg once daily thereafter.²⁰ Doses should be infused over one hour.

Dosage adjustments of oral itraconazole are not needed in patients with renal impairment. However, the IV formulation is solubilized by the addition of hydroxypropyl-b-cyclodextrin, which is excreted unchanged in the urine. This substance was found to produce pancreatic adenocarcinomas in rats. Therefore, IV itraconazole is contraindicated in patients with severe renal dysfunction (CrCl <30 ml/min).²⁰ There are currently no recommendations regarding dose adjustments in patients with hepatic impairment. A small study using the capsule formulation did not show significant alterations in the area under the time-concentration curve (AUC) of itraconazole in patients with cirrhosis, but the peak concentration was reduced by 47% and the elimination half-life had a two-fold increase.¹⁹

The oral solution has a higher bioavailability than the capsule formulation. The capsule is to be taken with food, while the solution has the best bioavailability on an empty stomach.^{18, 19, 25} The absorption of capsules can be enhanced by administering it with an acidic beverage such as a can of cola.²⁵ Since the pH of the solution is 2, cola is not recommended to enhance absorption of the oral solution.²⁷

Limitations (Drug Interactions and Absorption)
There are several drawbacks to therapy with itraconazole, including drug interactions and issues surrounding the absorption of oral itraconazole.

Drug interactions with itraconazole occur by two major mechanisms. It inhibits CYP3A4 which is an isoenzyme involved in the metabolism of many other medications. Because of this, itraconazole is contraindicated with the concomitant administration of terfenadine, astemizole, triazolam, lovastatin, and simvastatin. Medications which can decrease the acidity of the stomach, such as antacids, proton pump inhibitors, and H2RAs, decrease the absorption of oral itraconazole.²⁰

Another issue of concern is that, as a result of frequent concomitant conditions, many patients who have aspergillosis also have hypochlorhydria and/or enteropathy, which may decrease the absorption of oral itraconazole.² There may be a need to monitor itraconazole levels if a lack of absorption is suspected.

Caspofungin
Caspofungin, the first approved drug in a new class of antifungal agents called echinocandins, is currently available as an injection. It is indicated for the treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies (i.e., amphotericin B, lipid formulations of amphotericin B, and/or itraconazole).²⁸ It has not been studied as initial therapy for invasive aspergillosis.

Mechanism of Action
Caspofungin inhibits the activity of the enzyme glucan synthase, which leads to an inhibition of the synthesis of beta-(1,3)-D glucan, which is important for cell wall integrity.²⁹ The echinocandins are unique among the other antifungal agents as they target the fungal cell wall, rather than the fungal cell membrane. Because the glucan is not present in mammalian cells, caspofungin may have less toxicity than other antifungal agents.

Efficacy
The FDA based its approval decision for caspofungin on very limited clinical data. It also considered the efficacy and safety of alternative therapies and the risk-benefit analysis when making the decision.²⁹ One reason it was approved with such limited data is that it is used in a patient population which is critically ill and has few therapeutic options for the treatment of Aspergillus.³⁰ In the New Drug Application, the efficacy of caspofungin from a non-comparative open label study of patients (n=63) with documented invasive aspergillosis who were either unresponsive or intolerant of previous therapies were compared to historical controls.²⁹ According to the expert panel, 41% (26/63) of patients who received at least one dose had a favorable response, compared with 38.5% (25/65) in the intent-to-treat analysis or 44.6% (25/56) in the clinically evaluable analysis. These data compare favorably to the results in the patients from the historical control group, who were either refractory to or intolerant of other antifungal therapies. In this group 19.8% (19/96) responded.

Adverse Effects
Adverse drug effects reported in patients treated with caspofungin include fever, phlebitis/thrombophlebitis, headache, nausea, vomiting, rash, skin flushing, mild liver function test elevations, and a case of anaphylaxis. Overall, caspofungin was generally well-tolerated in the limited patient population who received it prior to approval (297 patients).

Dose/Administration
The dose for caspofungin is 70 mg loading dose on day 1, then 50 mg daily thereafter.28 The dose may be increased to 70 mg daily if the clinical response is poor. The dose needs to be decreased in patients with hepatic dysfunction. Caspofungin is administered by the intravenous route and should be given slowly over an hour.

Limitations (Drug Interactions)
One major drawback to therapy with caspofungin is the lack of information on drug interactions. Although the package insert states that it is not an inhibitor of any enzyme in the cytochrome P450 system, is not a substrate for P-glycoprotein, and is a poor substrate for cytochrome P450 enzymes, it has several drug interactions with medications which are known to interact with the P450 system.28 There are no data from formal drug interaction studies. However, it is thought that coadministration of inducers of drug clearance and/or mixed inducer inhibitors may result in clinically significant reductions in caspofungin concentrations. Based on results from a small number of patients who received caspofungin with efavirenz, nelfinavir, nevirapine, phenytoin, rifampin, dexamethasone, or carbamazepine, clinically significant reductions in caspofungin serum concentrations were observed. The mechanism of these interactions is not stated. In clinical studies caspofungin did not induce the CYP3A4 metabolism of other medications. The package insert suggests considering an increase in the caspofungin dose to 70 mg daily when co-administered with these interacting agents if the patient is not clinically responding.

Co-administration of caspofungin and tacrolimus reduced tacrolimus levels, so standard monitoring of tacrolimus blood concentrations and appropriate dosage adjustments are recommended.

Of the four healthy subjects who received caspofungin with cyclosporine, three developed transient elevations of alanine transaminase (ALT) that were 2 to 3 times the upper limit of normal. Two of eight patients in another group who received the two drugs concomitantly also had elevations of ALT, slightly above the upper limit of normal. In addition, cyclosporine increases the area under the curve (AUC) of caspofungin by approximately 35%. Co-administration of caspofungin and cyclosporine is not recommended until further information on the interaction is available.²⁸

Combination Therapy
Little information is available regarding the use of azoles, flucytosine, or rifampin in combination with amphotericin B, itraconazole, or caspofungin. The role and efficacy of such combinations is not established in the treatment of IA. Potential problems may actually occur with the concurrent use of these drugs. The use of rifampin and itraconazole is limited by drug-drug interactions, and the use of flucytosine may exacerbate myelosuppression in neutropenic patients. It may also be difficult to maintain nontoxic blood levels of flucytosine should the amphotericin B cause nephrotoxicity that may impair the excretion of flucytosine. The data regarding whether the combination of amphotericin B with itraconazole is antagonistic or synergistic are conflicting and clinical studies are needed.^31-33 Studies of caspofungin in combination with amphotericin B suggest no antagonism; however, the clinical significance is unknown since it has not yet been studied in humans.²⁸

Cost of Therapy
Along with efficacy and adverse effects, cost of therapy must also be considered. Table 2 lists the weekly cost of therapy for each agent. When well tolerated, the conventional amphotericin B product remains the cost-effective choice. However, when the infection is refractory to amphotericin therapy or when the patient can not tolerate conventional amphotericin B due to nephrotoxicity, consideration must be given to the other agents.

Duration of Therapy
There are no guidelines regarding the duration of therapy or total amphotericin B dose for the treatment of IA. Clinical judgment should be used when deciding the duration and should include consideration of factors such as response to therapy, the extent of infection, and the patient's underlying disease or immune status. In general, the treatment should be continued until clinical and radiographic abnormalities are resolving, cultures (if found initially to be positive) are negative, and any predisposing factors have subsided.²

Summary
As presented in this article, there are several options for treating invasive aspergillosis. However, conventional amphotericin B is still the preferred first line therapy based upon clinical experience and cost. ABLC and caspofungin both serve as second line therapies for patients intolerant of or refractory to conventional amphotericin B. The advantage of ABLC is that more clinical experience has been attained regarding efficacy, nephrotoxicity, and drug interactions. Caspofungin, on the other hand, has demonstrated less nephrotoxicity, but its side effects, drug interactions, and efficacy are less well established. Oral itraconazole is useful for continuation of therapy in patients who can take oral medications, are likely to be adherent, have good absorption, and are not receiving interacting medications. The role of intravenous itraconazole in the treatment of invasive aspergillosis is yet to be defined.

References

1. Clin Infect Dis 1998; 26: 781-805.
2. Clin Infect Dis 2000; 30:696-709.
3. J Am Soc Nephrol 1995;6:154-64.
4. J Antimicrob Chemother 1994;33:203-13.
5. Arch Intern Med 1988; 148; 2389-94.
6. J Clin Pathol 1988;41:494-7.
7. Am J Med 1989;87:547-52.
8. Br Med J 2001; 322:1-6.
9. Am J Kidney Dis 1998;31:780-5.
10. Clin Infect Dis 1998;27:603-18.
11. Bone Marrow Transplant 1997;19:343-7.
12. Clin Infect Dis 1998;26:1383-96.
13. J Antimicrob Chemother 1999;44:569-72.
14. Pediatr Infect Dis 1999;18:702-8.
15. Blood 1995;86:849a.
16. Abelcet® injection package insert. 1999
17. Clin Infect Dis 1996;22:315-21.
18. Sporanox® oral solution package insert. 2001
19. Sporanox® oral capsules package insert. 2001
20. Sporanox® injection package insert. 2001
21. Am J Med 1994;97:135-44.
22. Arch Intern Med 1997;157:1857-62.
23. Clin Trans 1998; 12:30-4.
24. Principles and Practice of Infectious Diseases, 5th ed. 2681.
25. Antimicrob Agents Chemother 1998;42:1862-5.
26. Eur J Clin Pharmacol 1997;52:235-7.
27. Personal communication, Ken Miller, Ortho Biotech Medical Information.
28. Cancidas® injection package insert. 2001
29. Background document for Antiviral Drug Products Committee Meeting NDA 21-227.
30. Transcript of FDA approval meeting 1/10/01.
31. Mycoses 1993; 36:421-4.
32. Diag Micro Infect Dis 1992;15:21-34.
33. Mycoses 1991; 34:281-5.

Reference	Study Design	Results
		Evaluable Clinical Response	Nephrotoxicity
12	Open-label, multicenter, emergency use study of ABLC in adult BMT patients with advanced systemic fungal infections who failed or were intolerant of amphotericin B N=95 patients with presumed or confirmed fungal infections Dose: 5 mg/kg/day	Response: Clinical N=59 Mycologic N=38 Aspergillosis 11/29 (38%) 9/20 (45%) Candidosis 14/20 (70%) 9/15 (60%) Fusariosis 2/3 (67%) --- Cryptococcosis 1/1 (100%) 1/1 (100%) Other 3/6 (50%) 0/2 (0%)	Withdrawal from therapy due to renal failure: n=2/95 (2.1%) Doubling of serum creatinine during ABLC therapy: n=12 (13.3%) of the 90 evaluable patients Mean duration of therapy: 25 days Mean cumulative dose: 6,314 mg
13	Open-label, single-patient, emergency use study of ABLC in patients who were refractory to or intolerant of conventional antifungal therapy. N=556 adult patients with proven or presumptive invasive mycoses (Some of these patients have been included in other publications.) Dose: 5 mg/kg/day	Complete or Partial Response Aspergillosis, overall 55/130 (42%) Disseminated 8/27 (30%) Pulmonary 28/74 (38%) Sinus 9/14 (64%) Single-organ 10/15 (67%) Yeasts, overall 74/105 (70%) Dimorphic fungi 11/15 (73%)	Greater than 20% increase in serum creatinine from baseline: n=132 (24%) Mean duration of therapy: 33 days Median cumulative dose 89 mg/kg
14	Open-label study of ABLC use in adult patients with invasive aspergillosis or candidiasis who were intolerant of conventional amphotericin B. N=10 patients Dose: 3 mg/kg/day	Response: Complete Partial Aspergillosis: Invasive 3/8 (38%) 1/8 (13%) Candidosis 2/2 (100%)	None.
15	Open-label, multicenter, emergency use study of ABLC in pediatric patients with invasive fungal infections refractory to or intolerant of conventional amphotericin B. N=111 pediatric patients (<18 years of age) Dose: 5 mg/kg/day	54 patients assessed for efficacy. Complete or Partial Response Aspergillosis, overall 14/25 (56%) Disseminated 2/7 (29%) Pulmonary 5/10 (50%) Sinus 5/5 (100%) Single-organ 2/3 (67%) Candidiasis, overall 22/27 (81%)	None. Mean duration of therapy: 38.9 days Mean cumulative dosage was 165.2 mg/kg
15	Open-label, multicenter, emergency use study of ABLC in adult patients with definite or probable invasive aspergillosis. Data was compared to historical control patients with aspergillosis who were treated with conventional amphotericin B. N=151 ABLC patients and 122 historical control patients Dose: 5 mg/kg/day ABLC	Overall response rates: ABLC: 40% Conventional amphotericin B: 23%	No specific information given.

BMT = bone marrow transplant

Table 2. Comparative Costs of Treatment for Invasive Aspergillosis
Drug	Dose
Amphotericin B	1 to 1.5 mg/kg QD or continuous infusion
Amphotericin B Lipid Complex	5 mg/kg QD
Caspofungin	70 mg load, then 50 mg QD
Itraconazole PO	200 mg BID
Itraconazole IV	200 mg BID x 2 days, then 200 mg QD

DRUGS ADDED TO STOCK

ETHANOLAMINE OLEATE
Injection: 5%, 2 ml ampule
Ethanolamine oleate (Ethamolin® - Questcor) is a mild sclerosing agent indicated for the treatment of esophageal varices that have recently bled, to prevent rebleeding. It replaces sodium tetradecyl injection, which was recently discontinued from marketing.

VALGANCICLOVIR
Capsules: 450 mg
Valganciclovir (Valcyte® - Roche) is an antiviral agent indicated as induction therapy and maintenance therapy for cytomegalovirus (CMV) retinitis in patients with AIDS.

ADDITIONAL ACTIONS

FLUOROURACIL TOPICAL SOLUTION
A 2% solution (Efudex®) has been added to stock.

GABAPENTIN ORAL SOLUTION
A 250 mg/5ml (Neurontin®) oral solution has been added to stock.

HYDROQUINONE SKIN BLEACHING MOISTURIZING CREAM
This product containing hydroquinone 4% and glycolic acid 10% (Glyquin®) has been added to stock.

HYDROXYPROPYLMETHYLCELLULOSE OPHTHALMIC SOLUTION
A 2.5%, 15 ml bottle (Goniosol®) has been added to stock. This product replaces the methylcellulose ophthalmic solution 2%, 15 ml bottle that was prepared by Pharmaceutical Services.

ISOSORBIDE MONONITRATE EXTENDED-RELEASE TABLET
A 30mg tablet has been added to stock.

PHENOL THROAT SPRAY
A 1.4% phenol throat spray (Chloraseptic®) has been added to stock.

PHENYLEPHRINE NASAL SOLUTION
A 0.5% strength (Neo-Synephrine®) has been added to stock. This product replaces the 0.125% and 0.25% solutions that have been discontinued by the manufacturer.

Note: The cost following each brief monograph is the UIHC acquisition cost.

  Title Page