fluconazole therapy for chronic disseminated candidiasis in patients with leukemia and prior...

Fluconazole Therapy for Chronic Disseminated Candidiasis in Patients with Leukemia and Prior Amphotericin B Therapy* ELIAS ANAISSIE, M.D., GERALD P. BODEY, M.D., HAGOP KANTARJIAN, M.D., CYNTHIA DAVID, M.D., Houston, Texas, KYLE BARNETT, M.D., Salt Lake City, Utah, ERIC BOW, M.D., Winnipeg, Manitoba, Canada, RICHARD DEFELICE, M.D., Sacramento, California, NANCY DOWNS, M.D., Campcity, Missouri, THOMAS FILE, M.D., Akron, Ohio, GEORGE KARAM, M.D., Baton Rouge, Louisiana, DAVID POTTS, M.D., Greenville, South Carolina, MARK SHELTON, M.D., Ft. Worth, Texas, ALAN SUGAR, M.D., Boston, Massachusetts

OBJECTIVE: To study the efficacy of fluconazole against chronic disseminated candidiasis (hepatosplenic candidiasis) in patients with leukemia in whom amphotericin B treatment had failed.

DEIGN: Retrospective analysis of patients with chronic disseminated candidiasis treated with fluconazole on a compassionate investigational new drug protocol.

SE~ITING: Multi-institutional. PATIENTSANDMEI’HODS: Twenty consecutive

patients received 100 to 400 mg of fluconazole per day for a median of 30 weeks. All had either failed to respond to treatment with more than 2 g of amphotericin B or had serious amphotericin B-related toxicities.

RESULTS: Fourteen of 16 evaluable patients (66%) responded. Responses were observed in seven of nine patients in whom adequate doses of amphotericin B had failed and in all seven patients who had amphotericiu B-related toxicities. In 12 patients, cytotoxic chemotherapy was continued without flare of the infection. Flucon- azole was well tolerated with rare side effects. AspezgiZhs superinfection developed in three patients and contributed to the death of two of them.

CONCLUSION: Fluconazole is a safe and effective agent with significant activity against chronic disseminated candidiasis.

*This is a rapid publication manuscript. From the Division of Medicine and the Division of Radiology (EA. GPB,

HK. CD), University of Texas, M.D. Anderson Cancer Center, Houston, Texas; Division of Infectious Diseases (KB), Department of Medicine, University of Utah, School of Medicine, Salt Lake City, Utah; Department of Oncology (EB), St. Boniface General Hospital, Winnipeg, Manitoba, Canada; Pulmonary Medicine Associates, Inc. (RD), Sacramento, Califor- nia; (ND), Camp City, Missouri; (TF), Akron, Ohio; Department of Medi- cine (GK), Memorial Hospital, Baton Rouge, Louisiana: Greenville Memo- rial Hospital (DP). Greenville, South Carolina; Cook Ft. Worth Children’s Medical Center (MS), Ft. Worth, Texas; and Section of Infectious Dis- eases (AS), University Hospital, Boston, Massachusetts.

Requests for reprints should be addressed to Elias J. Anaissie. M.D., The University of Texas, M.D. Anderson Cancer Center, Box 47. 1515 Holcombe Boulevard, Houston, Texas 77030.

Manuscript submitted April 23, 1991, and accepted in revised form May 28, 1991.

D uring the past decade, progress has been made in the treatment of patients with acute leuke-

mia, and the proportion of patients achieving complete remission and longer survival has increased [l-5]. A significant number of patients still fail to achieve complete remission, and the most fre- quent cause of treatment failure remains infection. Fungi-particularly Candida spp.-are responsible for most of the fatal infections [6-lo]. Disseminated candidiasis in this patient population includes both an acute and a chronic presentation. Acute disseminated candidiasis may be sudden in onset, associated with skin lesions, fungemia, and hypotension, and usually evolves over days, while the chronic form of the infection extends over several months and is characterized by progressive debilitation. Despite these differences, the acute and chronic forms of disseminated candidiasis are extreme forms of a continuous spectrum. While it is believed that the chronic syndrome follows an acute infectious episode, it may also convert into an acute infection when the patient’s immune status deterio- rates further. One chronic form of disseminated candidiasis has now emerged as a significant problem among patients undergoing remission induction chemotherapy or bone marrow transplantation for acute leukemia [ll-171. This syndrome, first described by Bodey in 1969, is referred to as hepatosplenic candidiasis [ 111. Chronic disseminated candidiasis (CDC) is a more appropriate descriptive term since the disease involves tissues other than liver and spleen and characteristically evolves over several months [Ml.

Typically, the infection begins during a period of prolonged neutropenia and presents as persistent fever, without discernible lesions. This stage proba- bly represents acute disseminated infection not de- tectable by currently available techniques. Stan- dard therapy with broad-spectrum antibacterial antibiotics is not successful, and fever persists even after the patient achieves a hematologic remission and his/her neutrophil count returns to normal. At that time, the patient’s serum alkaline phosphatase

142 August 1991 The American Journal of Medicine Volume 91

FLUCONAZOLE FOR DISSEMINATED CANDIDIASIS / ANAISSIE ET AL

level becomes elevated, and he/she may complain of abdominal pain. Hepatomegaly, splenomegaly, and abdominal tenderness may be detected in some patients. The diagnosis can be established by demonstration of multiple abscesses in the liver, spleen, and kidneys on ultrasound or computed tomography examination (CT scan) [12-191. Histopatholog- ic examination of biopsy specimens reveals the presence of granulomas usually containing fungal elements, but the organism often cannot be isolated from cultures of these biopsy specimens [12-M].

This infection (1) has been reported with increasing frequency, (2) is responsible for significant de- lays in the therapy for the underlying malignancy, (3) is highly fatal without therapy, and (4) is difficult to diagnose and treat and frequently requires long-term combination chemotherapy with amphotericin B plus Wlucytosine [12-191. This combination is toxic, costly, and inconvenient since it requires the intravenous administration of drugs, frequently in a hospital setting, and necessitates constant monitoring. Only 50% of patients respond to amphotericin B with or without Sflucytosine, with a significant number of patients succumbing to infection despite antifungal therapy [12-M].

ence of abdominal signs and symptoms such as upper abdominal pain or tenderness, jaundice, hepatomegaly, and/or splenomegaly; (4) elevations in liver function tests, particularly serum alkaline phosphatase; (5) abnormal findings on abdominal imaging (ultrasound, CT, or magnetic resonance imaging) consistent with the diagnosis of CDC as previously reported [38-401; (6) histopathologic demonstration of fungal elements in tissues consistent with Candida spp. [13,19]; (7) no clinical or laboratory evidence of other infections and/or clinical conditions that could account for the aforemen- tioned findings; and (8) failure to respond to 2 g or more of amphotericin B, or intolerable toxicity, and clinical and laboratory evidence of ongoing fungal infection prior to the initiation of treatment with fluconazole.

Fluconazole is a well-tolerated triazole that is available orally and intravenously and is effective in the treatment of fungal infections including those due to Candida spp. [20-371. In this report, we de- scribe the results with fluconazole in 20 leukemic patients with CDC who had either failed to respond to treatment with amphotericin B or who had serious amphotericin B-related toxicities. Fluconazole was well tolerated and produced clinical responses in 14 of 16 evaluable patients, including those refractory to amphotericin B.

The presence of many acute inflammatory cells on fine-needle aspiration in two patients who fulfilled all other diagnostic criteria but could not undergo biopsy because of high surgical risks was accepted. Because of the disseminated nature of the infection, histopathologic and/or microbiologic evidence of candidal infection in sites other than liver or spleen (such as blood and skin biopsies) was considered acceptable for diagnosis if patients fulfilled all of the other diagnostic criteria. Because of the low yield of organ culture and because the afore- mentioned combination of clinical, biochemical, radiologic, and histologic findings is considered diagnostic of this disease entity in this patient population [12-191, microbiologic documentation of Candida spp. in otherwise sterile sites was not required for diagnosis.

PATIENTS AND METHODS

Patients were excluded if they had previously experienced an adverse effect to fluconazole or were receiving systemic chemotherapy with any other antifungal agent.

Method of Study Fluconazole therapy was available through a

Pfizer pharmaceutical compassionate investigational new drug protocol 056-152. Consecutive patients with a diagnosis of leukemia and CDC who failed to respond to or could not tolerate amphoteri- tin B were analyzed. No patient who was offered fluconazole treatment for CDC declined therapy. No patient who fulfilled the eligibility criteria for study entry was rejected by the institutional review boards of the various institutions or by the clinical monitor at Pfizer Pharmaceuticals.

Pretreatment and Follow-Up Evaluation

Eligibility criteria for analysis required: (1) a diagnosis of acute leukemia or chronic myelogenous leukemia in blast crisis; (2) fever for 2 weeks or longer unresponsive to broad-spectrum antibacterial antibiotics while neutropenic, with fever persist- ing after recovery from neutropenia; (3) the pres-

Pretreatment evaluation included history and physical examination, pregnancy test in females, and evaluations of hematologic parameters (hemo- globin, platelet count, white blood cell and differen- tial counts, prothrombin time, partial thromboplas- tin time), liver function (aspartate aminotransferase, total and direct bilirubin, alkaline phosphatase), and kidney function (serum urea nitrogen, creatinine). Patients were examined daily when hospitalized and at least twice monthly there- after until the end of therapy or at the most recent visit to the clinic. Adverse or toxic reactions to fluconazole were assessed by clinical observation and bimonthly laboratory monitoring of hematologic, renal, and hepatic functions. Appropriate roentgen- ographic examinations of the sites of infection in-

August 1991 The American Journal of Medicine Volume 91 143

chiding ultrasound, CT scan, and/or magnetic resonance imaging of abdomen were done before treatment and at various intervals during follow- up. Diagnostic biopsy specimens and/or aspirates of involved sites were obtained in all patients.

Treatment Regimen Informed consent was obtained from all patients

according to institutional policies. In adults, fluconaxole was given as a single 400-mg oral loading dose, followed by 200 mg once daily, usually in the morn- ing. The dose was increased to 400 mg daily in nine patients who did not show clinical signs of improvement after 7 days of therapy. Two patients received a reduced dose of 100 mglday because of a creatinine clearance of less than 50 ml/minute following amphotericin B therapy. Patients in whom oral therapy could not be used received the first several doses intravenously. Duration of therapy was indi- vidualized based on the investigator’s clinical judg- ment because of the uncertainty regarding the appropriate duration of therapy for CDC.

Response Criteria Patients were evaluable for response if they met

the eligibility criteria and had completed a 2-week course of fluconazole. Because of the chronic nature of the infection and its slow response to therapy, patients were not considered evaluable for response if they had received treatment for less than 2 weeks unless their infection had progressed with therapy during this 2-week period. All patients were evaluable for toxicity.

Complete response indicated the disappearance of all signs and symptoms of infection, with disappearance of all known lesions by physical and roent- genographic examinations and no development of new lesions. Patients who showed persistent but significantly decreasing abnormalities on CT scan examination were not considered to have achieved a complete response even if all signs and symptoms of infection had completely resolved. Patients who died and showed no evidence of candidiasis after complete autopsy examination were considered to have achieved a complete response.

Partial response indicated the disappearance of all signs and symptoms of infection and normaliza- tion of liver function tests and ultrasound studies but persistence of residual lesions seen on CT scan. If biopsy samples of these lesions did not show candidal infection on histopathology and/or culture, the patient was then considered to have a complete response if there were otherwise no clinical or laboratory evidence of residual or persistent infection 6 months after discontinuation of fluconazole.

Failure indicated persistence or progression of the clinical, biochemical, and/or radiologic parameters of infection such as the appearance of new lesions, persistent fever, or deteriorating clinical condition.

RESULTS As of December 1990, 20 eligible leukemic pa-

tients were enrolled in the study. Sixteen of the 20 patients entered were evaluable for response, and all 20 patients were evaluable for toxicity. Four patients were not evaluable for response for the following reasons: (1) lost to long-term follow-up after 4 weeks of fluconaxole (one patient who was responding to fluconaxole), and (2) inadequate trial (three patients). One of these three patients received 1 week of fluconazole and died of unrelated causes. The second patient improved clinically after 10 days of fluconaxole but had to be taken out of the study because of the development of non-A, non-B hepatitis and concern that fluconaxole might aggravate hepatic impairment. In the third patient, fluconazole was started after the patient had already achieved a partial response to 2.6 g of amphotericin B. This patient was excluded from the analysis because evidence of persistent infection was only biochemical and radiologic and the patient appeared to have clinically improved with amphoteri- tin B. The patient achieved and maintained a complete response while taking fluconaxole.

Patient Characteristics Pretreatment characteristics of the evaluable pa-

tients are indicated in Table I. Seven patients were female and nine were male. The median age at entry was 43 years (range: 3 to 72 years). All patients had acute leukemia (myelogenous in 11, lymphoblastic in five). Except for Patient 6, who had myeloid blast crisis of chronic myelogenous leukemia, all patients were in hematologic remission at the time of initiation of treatment with fluconaxole. The clinical, biochemical, radiologic, and histopathologic features of all these patients were characteristic of CDC. Only five of the 16 evaluable patients had disease limited to the liver and spleen. Eight patients had microbiologic documentation of infection by Candida spp. Candida albicans was isolated from four patients, C. tropicalis from three patients, and C. parapsilosis from one patient. Except for Patient 11, who developed an anaphylactic reac- tion to the amphotericin B test dose, 14 adult patients had received amphotericin B for a median dose of 2.1 g (mean: 2.96 g; range: 0.3 to 17.3 g). Patient 8 had clinically and microbiologically documented candidiasis after two courses of amphoteri-




TABLE I

Patient Characteristics

Age Underlying and Disease and

Patient Sex Status Clinical

Presentation Sites

Involved Basis for

Diagnosis Prior

Treahnent

Evidence of Infection at

Initiation of FLU

14 29F AML-CR

15 68M AML-CR

16 29F AML-CR

27M ALL-CR

AML-CR

AML-CR

43M

33M

51M

42M

68F

72F

58M

37M

3F

ALL-CR

AML-CR

CML-BC

ALL-CR

AML-CR

AML-CR

AML-CR

AML-CR

ALL-CR

ALL-CR

Fever, pneumonia, abdominal pain

Fever, abdominal pain, hepatomegaly

Fever, abdominal pain




Fever! abdominal pain, skin nodules

Fever, abdominal pain, hepatomegaly, skin nodules, pneumonia




Fever, hepatosplenomeg- ah

Fever, hepatosplenomeg- ah

Fever, abdominal pain, hepatosplenomegaly

Hepatomegaly, fever


Liver, spleen, lungs

Liver, spleen

Liver, spleen, kidneys, blood

Liver, spleen, kidneys

Liver, spleen, kidneys, lungs, thyroid

Liver, spleen

Liver, spleen, kidneys, blood, skin

Liver, spleen, kidneys, lungs, eyes, skin, blood, others

Liver, spleen

Liver, spleen


Liver, spleen

Liver, spleen, kidneys


Liver, spleen, skin, kidneys, blood

Liver, skin, kidney

Clinical picture: LFT, (t) AmB* 2.lg CT,(t) US,(t) MRI, (t) Bx (liver)

Clinical picture: LFT, (t) AmB*0.3g CT,(t)US,(t)cytology (liver)

Clinical picture: LFT, (t) AmB* 1.14g CT,(t) US,(t) MRI, (t)culture blood, (t) cytology liver

Clinical picture: LFT, (t) AmB* 0.65g US,(t) CT,(t) MRI, (t) Bx (liver)

Clinical picture: LFT, (t) AmB* 5g, t5FCf (3 US,(t) CT, (t) Bx months), splenectomy (spleen, thyroid), (t ) culture (thyroid)

Clinical picture: LFT, (t) AmB* 0.85g US,(t)CT,(t)cytol- oey (liver)

Clin’Eaipict;re: LFT, (t) AmB* 0.85g CT,(t) Bx (skin), (t) culture (skin, blood)

Clinical picture: LFT, (t) AmB* 7.475g, +5FC+ (4 US,(t) CT, (t) Bx months), liposomal (liver, skin), (t) Cul- AmB 9.B4g ture (blood, skin)

Clinical picture: LFT, (t) AmB* 0.52g US, (t) Ga scan, (t) Bx (liver)

Clinical piciure: LFT, (t) AmB* 3g CT,(t) Bx (liver), (t) Culture (liver)

Clinical picture: LFT, (t) Anaphylaxis with AmB* CT, (t ) BX (liver) test dose

Clinical picture: LFT, It) AmB* 2.5g, splenectomy CT,(t) US,(t) Bx (spleen)

Clinical picture: LFT, (t) AmB* 23mg/kg, t 5FC CT,(t) US,(t) Bx (2 weeks) (liver), (t) culture (liver)

Clinical picture: LFT, (t) *AmB 3g, +5FCf(l CT, (t ) Bx (spleen) month), splenectomy

Clinical picture: LFT, (t) AmB* 2.lg CT,(t) culture (blood)

Clinical picture: LFT, (t) AmB* 2.lg CT,(t) Bx (liver), (t) culture (skin, liver)

Fever, LFT, (t) CT, (t) US, (t) Bx (liver)

Fever, abdominal pain LFT, (t) CT, (t) US

Fever, abdominal pain, LFT, (t) CT, (t) US, (t ) cytology liver

Fever, abdominal pain, LFT,(t)CT,(t)US, (t) Bx liver

Fever,(t) US, (t) CT, (t)Bxandculture (thyroid) (t) Bx (liver)

Fever, abdominal pain, LFT, (t) US, (t) CT, (t) cytology liver

Fever,(t) CT,(t) Bx (skin), (t) culture (skin, blood)

Fever, abdominal pain, endophthalmitis, skin lesions, LFT, (t) CT, (t) US, (t) Bx and culture skin, (t) Bx liver

Fever, LFT, (t) US

Fever, LFT, (t ) CT

Same as presentation

Fever, LFT, (t) CT, (t) Bx (spleen)

Fever, hepatosplenomeg- sly,(t) CT

Fever, LFT, (t) CT, (t) Bx (soleen)

Fever,‘abdom’inal pain, LFT, (t) CT

Fever, abdominal pain, LFT, (t) CT

( = biopsy (histopathology); ALL = acute lymphcqtic leukemia; AML = acute myelogenous leukemia; CML-BC = chronic myelogenous leukemia in blast crisis; CR = complete remission; US = trasound; CT = computed tomographic scan; MRI = magnetic resonance imaging; LFT = increased liver function tests; GA = gallium. imphotericin 6, grams. i-flucytosine.

tin B plus Ulucytosine and two courses of liposo- tion in two patients, life-threatening anaphylaxis in ma1 amphotericin B, for a 17.3-g cumulative one patient, and persistent severe, shaking chills amphotericin B dose. A 3-year-old patient had and high-grade fevers despite optimal supportive failed to respond to 23 mg/kg of amphotericin B care in four patients. Days from diagnosis to entry combined with 2 weeks of 5-flucytosine. Flucona- into study varied from 1 to 315 days (median: 32; zole was started in nine patients because of lack of mean: 83). All patients had clinical and laboratory response to amphotericin B (greater than 2 g in evidence of persistent or progressive infection at adults, 23 mg/kg in one child), while seven patients the time of initiation of fluconazole. Three of the received fluconazole because of intolerable ampho- eight patients with microbiologic documentation of tericin B-related toxicities including renal dysfunc- Candida spp. had positive cultures at the time of



TABLE II

Patient Treatment and Outcome

Fluconazole

22 Duration Chemotherapy Status of

Follow-Up and Leukemia on Final Patient he) (weeks) Response (months) Neutropania Fluconazole Outcome

1 400 56 Complete 26t Yes Remission Alive and well; no evidence of infection 15 months after discontinuation of fluconazole

2 400 60 Partial 21t YC?S Remission Alive and well; continues to respond 10 months after discontinuation of fluconazole

3 400 57t Partial 16t Yes Relapse Alive and well; continues to respond 6 months after discontinuation of fluconazole

4 400 2385

Partial 8 Yes Relapse Died of aspergillosis and progressive leukemia 5 400 Complete 11 Yes Relapse Died of progressive leukemia, streptococcal sepsis, and disseminated

aspergillosis; no evidence of candidiasis at autopsy examination

F 400

100-200 Et ;gy

A Yes Relapse Died of progressive leukemia and massive gastric bleeding Yes Remission Alive and well; continues to respond 6 months after discontinuation of

fluconazole

i 400 11 Fail

It Yes Relapse Died of leukemia and persistent candidiasis

200 5t Partial Yes Relapse Died of leukemia; no evidence of candidiasis 4 months after discontinuation of fluconazole

10 200 15 Partial 13 Yes Relapse Despite response tofluconazole, patient switched to amphotericin B prior to reinduction chemotherapy; died 10 months later without evidence of Candida infection

11 200 9 Partial 21t Yes Remission Fluconazole resumed for 12 weeks after reinduction chemotherapy; alive and well, continues to respond 18 months after discontinuation of fluconazole

12 200 9 Complete 18t No Remission Alive and well; no evidence of infection, continues to do well 22 months after discontinuation of fluconazole

13 6-12mgIkg 45 Complete 2ot Yes Remission Alive and well; no evidence of infection 14 months after discontinuation of fluconazole

14 400 19 Complete 14 Yes Remission Died of streptoccccal sepsis; had two pulmonary abscesses (0.5 cm each) consistent with aspergillosis; no evidence of Candida infection at autopsy

15 100 13 Complete 271 No Remission Alive and well; no evidence of infection 24 months after discontinuation of fluconazole

16 400 30 Fail 8 Yes Relapse Died with candidiasis

initiation of fluconaxole. Three patients (Patients 5, 12, and 14) underwent splenectomy, which revealed persistence of the fungal infection despite treatment with amphotericin B. At the time of splenectomy, all three patients had clinical and laboratory evidence of persistent infection at sites other than the spleen, thus enabling us to assess the response to fluconaxole at these sites. No patient received other antifungal agents while receiving fluconaxole. All patients were managed as outpatients except when concurrent illnesses unrelated to candidiasis necessitated hospital admission. The period of follow-up from the time of diagnosis of the entire co- hort of 16 evaluable patients was from 4 to 31 months (median: 18 months; mean: 18 months). The median time of follow-up after discontinuation of fluconazole in the eight patients who are still alive was 14 months (mean: 14 months; range: 6 to 24 months), a somewhat brief duration to assess risk of relapse.

The patients’ treatments and outcomes are shown in Table II. The median duration of treatment was 30 weeks (range: 9 to 75 weeks). Overall, seven patients (44%) achieved a complete response and seven other patients (44%) had a partial response, for an overall response rate of 88%. In six

patients (four complete responders and two failures), response was also documented by histopathologic examination of previously infected sites. Liver biopsies of two patients with clinical response (percutaneous in Patient 13 and open in Patient 15) showed no evidence of infection despite serial sec- tioning of the specimens to ensure that no fungal elements were present. Both patients are alive without evidence of infection 14 and 24 months after discontinuation of fluconazole. In addition, two patients (Patients 5 and 14) had no evidence of candidal infection at autopsy, while candidiasis was still present in Patient 16 on liver biopsy and in Patient 8 at autopsy. The median time to achieve a significant clinical improvement was 2 weeks (range: 2 to 8 weeks). Response was seen in one patient who received 100 mg daily, in all five patients who received 200 mg daily, and in seven of nine patients who received 400 mg daily. The child who received a 12 mg/kg daily dose also responded. C. albicans infection relapsed following leukemic relapse and neutropenia in Patient 5 and responded to a dose increase from 200 to 400 mg daily of fluconazole. Therapy was considered to have failed in Patients 8 and 16. Patient 16 had chronic disseminated C. albicans infection that failed to respond to 2.1 g of


amphotericin B and had persistence of fever, abdominal pain, radiologic findings of infection, and increase in serum alkaline phosphatase. Following the administration of fluconazole, her fever decreased, her general well-being significantly improved, and a significant radiographic improvement in the number and size of abdominal lesions was noted. During therapy, the patient’s leukemia relapsed with subsequent neutropenia. Repeat abdominal ultrasound revealed continuous regression of kidney and splenic lesions but also the appearance of new hepatic lesions compatible with candidiasis. Treatment with amphotericin B was restart- ed, but the patient showed no response and died with candidiasis. Three responding patients developed invasive mold infection: sinopulmonary aspergillosis (Aspergillus ~Zauus) in Patient 4 and disseminated aspergillosis (A. ~~auus) in Patient 5, and two O.&cm pulmonary lesions at autopsy consistent with aspergillosis in Patient 14. During treatment with fluconazole, Patients 4 and 5 had leukemic relapses unresponsive to multiple courses of cytotoxic chemotherapy and had 6 and 8 months, respectively, of persistent, profound neutropenia and a high number of circulating blasts. In these three patients with superinfection, we ruled out Aspergil- Zus spp. as the cause of the original syndrome by the recovery of Candida spp. from an infected site in one patient and the absence of characteristic asper- gillar morphology at biopsy examination in all three patients (i.e., acute-branching septate hyphae). In addition, the clinical and laboratory picture in all three patients was most compatible with that of CDC [13]. Among the nine patients who had initial- ly failed to respond to adequate doses of amphoteri- tin B, seven responded to fluconazole (complete response in six and partial in one). All seven patients who could not tolerate amphotericin B responded to fluconazole (complete response in two and partial in five). Three of the four patients infected with C. ulbicuns and two of the three patients infected with C. tropicalis responded to fluconazole. “Breakthrough” candidal infection occurred in one patient whose infection was caused by C. albicans; dose escalation and recovery from myelo- suppression brought his infection under control. Twelve of the 14 patients subsequently received cytotoxic chemotherapy with consequent neutropenia; they continued to respond to fluconazole. Furthermore, there was evidence of deterioration in the host’s underlying disease and, hence, immune status, after discontinuation of amphotericin B and initiation of fluconazole in eight patients (Patients 3, 4, 5, 6, 8, 9, 10, and 16). These patients were in complete hematologic remission during treatment with amphotericin B and had a leukemic relapse

several weeks after initiation of fluconazole. De- spite the lack of hematologic improvement with antileukemic therapy, six of these eight patients continued to clear their candidal infection while two patients had progressive infection after a period of clinical improvement.

Toxicity Toxicity encountered with this therapy was mini-

mal. Nausea was the only toxic effect and occurred in four patients. Reduction in the fluconazole dose from 400 mg to 300 mg was necessary in one patient (Patient 2) without any apparent effect on response. Laboratory studies did not reveal any drug- related hematologic, renal, or hepatic abnormalities. The elevated liver function tests that accompanied the clinical picture of CDC progres- sively improved with fluconazole therapy as a result of eradication of the infection.

COMMENTS This report represents the largest series of pa-

tients with CDC in a well-defined patient population (i.e., patients with acute leukemia receiving chemotherapy). Fluconazole appeared to be effective, particularly when given as a 400-mg daily dose. Several of these patients had failed to respond to large doses of amphotericin B or had large fungal abscesses, thus confirming the potential of fluconazole to induce responses in advanced disease. It is also important to keep in mind that most patients in this series who had a partial response continue to do well several months after discontinuation of fluconazole. Given the known slow radiologic response in CDC, partial responders may ultimately achieve a complete response even after discontinuation of antifungal therapy. Cytotoxic chemotherapy was continued in the majority of patients without recru- descence of infection. This is important because the course of the underlying leukemia may not allow therapeutic delay. Fluconazole was also well tolerated compared with the preceding amphotericin B therapy. Fluconazole did not exacerbate liver function test abnormalities, even in the presence of infection-related biochemical liver dysfunction, an important finding, since fluconazole has reportedly been associated with hepatic dysfunction in some settings. Therapy was given once daily orally in an outpatient setting, a convenient and less expensive approach to such a chronic illness [35]. Our results are in agreement with studies demonstrating the anticandidal activity of fluconazole in animal models and on a limited basis in humans [20-351. Flu- conazole was found useful in the prevention and treatment of CDC in a rabbit model of infection [34,35]. In a recent study, all six leukemic patients



with CDC in whom amphotericin B therapy had failed responded to fluconazole, despite continuous immunosuppression in five of them [37].

Amphotericin B failures in CDC have been previously reported [12-191. A literature review from two recently published series indicated that the mortal- ity rate was “still very high even with adequate treatment” [12], with only “54% of the patients responding to amphotericin B” [13]. It is encouraging that seven of our nine patients (78%) treated following failure of amphotericin B responded to fluconazole. Equally important is the group of patients who manifested serious amphotericin B toxicities, a common occurrence, and who responded to fluconazole. Additional experience is needed, however, before fluconazole could be used as first-line therapy. It is possible that early use of combination antifungal therapy-amphotericin B, high-dose fluconazole, and 5-flucytosine-may have improved the response in our two refractory patients. This approach is currently being investigated at our insti- tution in patients with CDC. Once a response to this induction phase (2 to 4 weeks) is obtained, amphotericin B is discontinued, the 800-mg daily dose of fluconazole is decreased to 400 mg, and the combination of fluconazole and 5flucytosine is then continued until a maximum response is achieved. Early results appear promising at the University of Texas, M.D. Anderson Cancer Center.

The prolonged course of this infection in this and other series highlights its chronic nature. The mul- tiorgan involvement with Candida spp. emphasizes its systemic spread. This contrasts with the focal nature of the infection suggested by the currently used terminology of “hepatosplenic candidiasis.” A more appropriate terminology, such as CDC, would better characterize this disease entity. This pro- posed change in terminology is not purely a seman- tic issue. Rather than focusing on a “hepatosplenic” infection, a disseminated process would imply care- ful clinical and laboratory evaluation of its extent and continuing therapy until infection at all sites, including extra-abdominal ones, has responded. Such a disseminated process would also imply that agents that distribute widely in body tissues should be given serious consideration for the treatment of this infection. While the complexity of the conditions of the individual patient cannot be repro- duced in animal models of infection, Cole et al [36] and Walsh et al [35] have developed animal models of chronic candidal infections mimicking-to a cer- tain extent-the clinical picture of “hepatosplenic candidiasis.” Both teams of investigators refer to their infection models as CDC [35,36]. We have previously referred to this entity as chronic systemic candidiasis [18]. Perhaps CDC would be preferable.

Questions may arise as to whether overlap exists between some of the features of CDC and those observed in acute disseminated candidiasis (ADC) and whether CDC represents the same disease process as hepatosplenic candidiasis. Significant overlap is expected between the features of CDC and ADC since both syndromes represent a continuum of disseminated infection with Cundidu spp. [l&35], with CDC following ADC, perhaps as the use of “early amphotericin B may be changing the pattern of disseminated candidiasis in some patients” [13,41]. Similarly, CDC may convert into ADC when the patient’s immune status deterio- rates further. An analogy can be made with the syndrome of graft-versus-host disease (GVHD) since chronic GVHD may be an extension of acute GVHD with a different clinical picture and yet significant overlap. Also, the clinicopathologic features of CDC presented in this series are no different from those reported in the literature describing hepatosplenic candidiasis. Both syndromes evolve over several months, respond poorly to amphoteri- tin B, have similar histopathoiogic findings, and have evidence of disseminated infection that may include bloodstream, kidneys, lungs, bile, liver, spleen, peritoneal fluid, cerebrospinal fluid, urine, pleural fluid, soft tissue, and heart, as reported in three recently published articles [12,13,19].

While it could be argued that despite clinical and laboratory evidence of ongoing infection in all our patients at the time of initiation of fluconazole, amphotericin B may have already induced major responses in the nine refractory patients, previous experience suggests otherwise. In fact, patients treated with amphotericin B doses similar to those in this study had such a high failure rate that rec- ommendations for using much higher doses in combination with 5flucytosine were made [13]. It is not unlikely, however, that amphotericin B could have caused some inhibition of growth, thus allowing fluconazole to exert its activity on an already-reduced fungal inoculum. Because of the long half-life of amphotericin B in humans, and the known additive or synergistic effect between amphotericin B and the triazoles, it is possible that an additive effect of amphotericin B and fluconazole may have occurred in patients who received greater than 2 g of amphotericin B. We cannot compare fluconazole with amphotericin B plus 5-flucytosine since our data were obtained from a group of patients who had failed to respond to amphotericin B. However, the need for intravenous drug administration and constant monitoring and the high cost and narrow therapeutic index of this combination render it undesirable for the prolonged therapy usually required in CDC. A significant proportion of such patients also re-



ceive other drugs with potential synergistic toxicities such as vancomycin, aminoglycosides, cis-plati- num, and/or cyclosporine [42-441. Promising results have also been obtained in studies with liposomal amphotericin B [45] or fluconazole [37].

It could be argued that a response to fluconazole, after an apparent failure to respond to amphoteri- tin B, may have occurred because of improvement in the host’s immune status coinciding with the administration of fluconazole. Quite the opposite occurred in this study: several patients showed evidence of leukemic relapse or became neutropenic from antileukemic therapy, while CDC still responded to fluconazole; these same patients had maintained complete hematologic remission during the preceding amphotericin B therapy. Similar findings were noted by Kaufman et al [37].

While a definitive documentation of invasive fungal infection such as CDC should ideally be based on histologic and microbiologic evidence of candidal infection, there are limitations to such an approach. Liver biopsy is not feasible in most of these patients because of their high surgical risks (throm- bocytopenia, coagulopathy). False-negative results, both histopathologic and/or microbiologic, are common because of sampling technique (especially with a percutaneous approach) or prior exposure to amphotericin B with consequent inhibition of growth [ 131. The literature on CDC reflects these problems, since most reports describing cases of “hepatosplenic candidiaais” included patients with no antemortem histopathologic or microbiologic documentation of candidiasis [12-171. Our yield with antemortem culture of Candida spp. (eight of 16, 50%) is similar to that obtained by Thaler et al (two of eight, 25%) [13], Haron et al (two of five, 40%) [12], and the cumulative experience of several institutions (40%) [18]. More rigorous eligibility criteria would select the patients with the best performance status and exclude the very ill (patients who cannot undergo invasive procedures) routinely seen in clinical practice, and the results of clinical trials with very narrow eligibility criteria may not be applica- ble to the community practice [46]. Furthermore, the clinical syndrome of CDC is quite characteristic: “persistent fever unresponsive to antibacterial antibiotics, abdominal symptoms, and elevated serum alkaline phosphatase levels in a patient with hematologic malignancy who has recently recov- ered from neutropenia” [13]. These characteristic clinical, radiologic, and histopathologic findings, together with the clinical and laboratory response to antifungal chemotherapy alone, establish the fungal etiology of the infectious process.

The occurrence of presumed or documented aspergillosis in three responders and the conflicting

results obtained in animal models of aspergillosis raise concern about the efficacy of fluconazole in preventing this infection [47-511. Two of our three patients had experienced multiple leukemic relapses and had been profoundly neutropenic for 6 and 8 months, respectively, prior to developing aspergillosis. In both patients, aspergillosis was a con- tributory cause of death. Hence, these patients may be considered initial responders but long-term failures because of the development of fatal aspergillosis. In such patients, preventing aspergillosis may be extremely difficult. Leukemic patients with much better prognostic factors (e.g., de nouo leukemia) have developed aspergillosis while receiving prophylactic intravenous amphotericin B at 0.5 mg/kg every other day [52]. Nonetheless, the potential emergence of aspergilli- and azole-resistant yeasts such as Cundidu krusei deserves a note of caution and emphasizes the need for combination antifungal chemotherapy, particularly in severely immunosuppressed patients who are at an increased risk of acquiring such refractory infections.

In conclusion, our data suggest that fluconazole therapy for CDC is effective and better tolerated than amphotericin B. The activity and safety pro- file of this drug, together with the convenience and lower cost of administering oral therapy once daily in an outpatient setting, indicate that fluconazole represents a potential alternative to amphotericin B in established CDC.

ACKNOWLEDGMENT We would like to acknowledge Dr. Lewts Weintraub for patient referral.

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