C A S E R E P R T S _

Caspofungin: A Potential Cause of Reversible Severe Thrombocytopenia

Julia Lynch, Pharm.D., and Annie Wong-Beringer, Pharm.D.

Caspofungin is an echinocandin agent approved for the treatment of invasivecandidiasis and refractory aspergillosis. Compared with amphotericin B,caspofungin has an improved safety profile, but clinical experience with thisagent is still accumulating. A 68-year-old man developed reversible severethrombocytopenia, possibly due to caspofungin, after being successfullytreated for Candida albicans endocarditis. Given the limited clinicalexperience with caspofungin, continued vigilance for unusual and seriousadverse events associated with the drug is imperative.Key Words: caspofungin, echinocandins, antifungal, thrombocytopenia.(Pharmacotherapy 2004;24(10):1408–1411)

Caspofungin is the first approved drug in anew class of antifungal agents called theechinocandins.1 It was recently approved by theFood and Drug Administration for treatment ofinvasive aspergillosis and candidiasis. It actsagainst Candida species by inhibiting synthesis ofb-(1,3)-D-glucan, a vital component of fungalcell walls. Caspofungin has a more favorableadverse-effect profile than amphotericin B.1

However, the overall safety data published to dateare limited to fewer than 1000 patients whoreceived single or multiple doses of the drug.1 Thus,continued postmarketing surveillance of drug safetyby clinicians is of paramount importance.

Case Report

A 68-year-old man was admitted to the hospitalfor shortness of breath, coughing, abdominalpain, and intermittent fever, which had persistedfor 10 days. His medical history was significantfor myocardial infarction, heart failure, hyper-tension, coronary artery disease, left-sidedcolectomy for carcinoma in situ, and right-sidedcolectomy for perforated diverticulitis. His drugtherapy consisted of aspirin, amiodarone,diphenhydramine, furosemide, levalbuterol,

lansoprazole, sodium bicarbonate, zolpidempotassium, lisinopril, promethazine, and atropinesulfate–diphenoxylate hydrochloride. Thepatient was transferred to the intensive care uniton hospital day 2 due to clinical deteriorationwith hypotension and an elevated troponin level.

On hospital day 3, the patient developedrespiratory failure requiring intubation whilereceiving empiric antibacterial therapy withpiperacillin-tazobactam and vancomycin. Twoblood cultures obtained on admission grewCandida albicans. An aortic valve vegetation of 2 x1.2 cm was noted on the echocardiogram, sup-porting the diagnosis of fungal endocarditis.Treatment with amphotericin B deoxycholate(AmBd) 0.4 mg/kg/day was started. The dosagewas later increased to 1 mg/kg/day, and flucytosine37.5 mg/kg every 8 hours was added to the regimen.

On hospital day 5, multiple infarcts in thebrain and kidney cysts appeared on a computedtomography scan, suggestive of septic emboli.After receiving combination antifungal therapyfor 5 days, the patient underwent an aortic valvereplacement and a two-vessel coronary arterybypass graft procedure. Two large vegetations onthe aortic valve with no annular destruction werenoted during surgery. Transfusions with 2 unitsof platelets and 4 units of packed red blood cellswere administered after surgery due to a transientdrop in platelet count, with gradual return tonormal over the ensuing 5 days.

From the School of Pharmacy, University of SouthernCalifornia, Los Angeles, California (both authors).

Address reprint requests to Annie Wong-Beringer,Pharm.D., University of Southern California, School ofPharmacy, 1985 Zonal Avenue, Los Angeles, CA 90033.

CASPOFUNGIN-ASSOCIATED THROMBOCYTOPENIA Lynch and Wong-Beringer

The patient showed a slow but steadilyimproving course after surgery. However, hisserum creatinine level doubled from his baseline(1 mg/dl) to 2 mg/dl during his treatment withAmBd. For this reason, amphotericin B lipidcomplex (ABLC) 300 mg/day was substituted forthe AmBd formulation, and the dosage offlucytosine was decreased to 37.5 mg/kg every 12hours. Unfortunately, cultures obtained atsurgery from blood and the aortic valve all grewC. albicans. Because the patient’s blood had notbeen sterile at the time of prosthetic valve place-ment, despite treatment with AmBd andflucytosine, his treatment regimen was changedto include caspofungin 70 mg for 1 day, then 50mg/day, as a substitute for flucytosine.

One week after the patient began receivingcaspofungin as a replacement for flucytosine, his

platelet count dropped precipitously from 136 x103/mm3 to 24 x 103/mm3, reaching a nadir at 3 x103/mm3 in 2 days (Figure 1). He was given 4units of platelets and 102 g of intravenousimmunoglobulin. At the same time, combinationtherapy of caspofungin and ABLC was discontinuedand replaced by fluconazole 600 mg/day. Aspirin,amiodarone, and heparin flush were alsodiscontinued. A bone marrow biopsy examinationwas normal, and the patient’s platelet countreturned to a level above 150 x 103/mm3 within10 days. An antiplatelet antibody test waspositive, whereas a specific test (enzyme-linkedimmunosorbent assay) for heparin-associatedantiplatelet antibodies was negative.

Amphotericin B lipid complex was restarted 4days after the nadir of the patient’s platelet count,due to a febrile episode with ventricular tachycardia

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Figure 1. Patient’s hospital course, correlating changes in platelet count with drugs administered. AmBd = amphotericin Bdeoxycholate; ABLC = amphotericin B lipid complex; AVR = aortic valve replacement.

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PHARMACOTHERAPY Volume 24, Number 10, 2004

and hypotension requiring vasopressors. Acomputed tomography scan 1 week after thethrombocytopenic event showed liver hematoma,a subdural hemorrhage with intracranial bleed,and a large thrombus in the abdominal aorta. Basedon a negative test for heparin-associated antiplateletantibodies, the patient was rechallenged withheparin therapy. A craniotomy eventually wasperformed.

The patient completed ABLC therapy after acumulative dose of 10 g. Fluconazole 400mg/day was started as long-term maintenancetherapy. The patient’s platelet count remainedabove 150 x 103/mm3 despite the reintroductionof heparin and ABLC. A follow-up transesophagealechocardiogram performed on hospital day 52showed mitral valve prolapse with 3+ mitralregurgitation and a normally functioning aorticvalve with no vegetation. The patient remainedin the hospital for management related torespiratory function and anticoagulation.

Discussion

Our patient developed severe thrombocytopeniacomplicated by intracranial hemorrhage andarterial thrombosis during treatment for fungalendocarditis. The timing of the adverse events inrelation to drugs prescribed likely points to adrug-induced process. Several of the agentsreceived by our patient have been associated withthrombocytopenia. Of these agents, flucytosinehas been implicated most frequently in drug-induced thrombocytopenia, followed by heparin,amphotericin B, and caspofungin.

Myelosuppression, such as leukopenia andthrombocytopenia, has been reported in up to60% of patients receiving flucytosine; patientswith a serum peak concentration exceeding 125µg/ml for 2 weeks or longer are particularly atrisk.2 The mechanism of toxicity is not fullyunderstood but is thought to relate to conversionof flucytosine to certain metabolites, such as 5-fluorouracil. Flucytosine was discontinued inour patient 1 week before the nadir of plateletcount. However, because our patient developedrenal insufficiency while receiving flucytosine,we cannot exclude the possibility that hisdelayed-onset thrombocytopenia was a toxiceffect of accumulated flucytosine. Based onpopulation pharmacokinetic parameters,3 thepredicted serum peak flucytosine concentrationwould have been 83 µg/ml on the last day of ourpatient’s therapy. Flucytosine clearance from thebody should have been completed 5 days before

our patient developed thrombocytopenia, basedon the drug’s predicted half-life of 10.5 hours.Thus, the contributing role of flucytosine to ourpatient’s thrombocytopenia is likely minimal,based on the timing of the event and expecteddrug concentrations.

Thrombocytopenia induced by heparin as aresult of platelet activation by heparin-dependentimmunoglobulin (Ig) G antibodies has beenreported to occur at varying frequencies.4 Criteriafor diagnosis include platelet count below 150 x103/mm3 and a positive test for heparin-dependent IgG antibodies.4 A drop in plateletcount typically occurs 2 weeks after the start oftherapy.

On the other hand, amphotericin B–inducedthrombocytopenia has been described rarely incase reports of adults and children.5–8 A plateletcount reaching a nadir at 30 x 103/mm3 wasdescribed in a patient with acute promyelocyteleukemia after 5 weeks of therapy withamphotericin B and flucytosine for hepaticcandidiasis.5 The patient’s platelet countreturned to normal within 10 days after discon-tinuation of therapy. After rechallenge withamphotericin B, thrombocytopenia recurredwithin 2 weeks and appeared to be caused bysuppression of platelet production rather thanperipheral destruction of platelets. Our patienttested negative for heparin-associated antibodiesand had a normal bone marrow examination.Thrombocytopenia did not recur after rechallengewith heparin and amphotericin B, providingstrong evidence for another cause. Of note, thepatient tolerated an additional 4800 mg of ABLCwith continued platelet recovery.

Caspofungin is a relatively new antifungalagent with a much improved safety profilecompared with amphotericin B.1, 9–11 Possibleadverse effects reported from clinical trials ofcaspofungin include fever and chills, phlebitis,hypertension, tachycardia, nausea, vomiting, andtachypnea.10, 11 Laboratory abnormalities, such ashyperbilirubinemia, hypokalemia, leukopenia,hypoalbuminemia, increased aspartate amino-transferase and/or alanine aminotransferaselevels, and decreased hemoglobin levels, havebeen observed.10, 11 Of note, the package insertstates that platelet counts decreased in 3.1% and1.5% of patients receiving dosages of 50 mg/dayand 70 mg/day, respectively. Those patients wereenrolled in phase II and III comparator-controlled clinical studies. However, themanufacturer did not provide details of theadverse events (i.e., degree and duration of

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CASPOFUNGIN-ASSOCIATED THROMBOCYTOPENIA Lynch and Wong-Beringer

thrombocytopenia).11

In our patient, caspofungin was discontinued,along with heparin flush and aspirin, on the daythrombocytopenia was first noted. After platelettransfusions and intravenous immunoglobulintherapy, the patient’s platelet count stabilized andreturned to normal, despite rechallenge withheparin and ABLC. These findings point tocaspofungin as a likely contributor to our patient’sthrombocytopenia.

Failure to sterilize the aortic valve and blood atthe time of surgery raised concerns for infectingthe newly placed prosthetic valve. Thus,caspofungin was added to our patient’s treatmentregimen to maximize the efficacy of antifungaltherapy in the presence of prosthetic materialsbased on its demonstrated activity against C.albicans biofilms.12 Combination therapyconsisting of caspofungin and amphotericin Bresulted in the successful treatment of prostheticvalve endocarditis with C. albicans. This wasdemonstrated by blood cultures, which remainedsterile, and by follow-up transesophagealechocardiogram, which showed no vegetation 42days after valve replacement.

These findings support the possible contributionof caspofungin to thrombocytopenia in ourpatient. Of particular significance is the reversalof thrombocytopenia after the patient discontinuedcaspofungin but continued or was rechallengedwith other potential causative agents. Thepresence of platelet antibodies and the normalbone marrow examination suggest peripheraldestruction of platelets rather than suppressionof platelet production as a likely mechanism bywhich caspofungin caused thrombocytopenia.

Conclusion

Caspofungin is a valuable agent that expandsour limited treatment options against invasivemycoses. However, given its limited clinicalexperience, continued vigilance for unusual andserious adverse events associated with caspofungintherapy is imperative. Caspofungin should beincluded in the differential as a possible cause ofdrug-induced thrombocytopenia.

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