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Diagnostic Microbiology and Infectious Disease xxx (2012) xxx–xxx
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Diagnostic Microbiology and Infectious Disease
j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / d i a g m i c r o b i o
Hepatic mucormycosis with abscess formation☆
Henry Su a, George R. Thompson III b, c, Stuart H. Cohen b,⁎
a
b
c
Department of Internal Medicine, University of California Davis Medical Center, University of California-Davis, Sacramento, CA 95817, USA
Division of Infectious Diseases, Department of Internal Medicine, University of California Davis Medical Center, University of California-Davis, Sacramento, CA 95817, USA
Department of Medical Microbiology and Immunology, Coccidioidomycosis Serology Laboratory, University of California-Davis, Davis, CA 95616, USA
a r t i c l e
i n f o
Article history:
Received 28 December 2011
Received in revised form 25 February 2012
Accepted 27 February 2012
Available online xxxx
a b s t r a c t
We describe a case of hepatic mucormycosis with abscess, an uncommon presentation of mucormycetes
infection. Our patient was initially treated with transcutaneous pigtail catheter placement, liposomal
amphotericin B, and micafungin without improvement. The patient subsequently improved after hepatic
segmentectomy and hemidiaphragm resection.
© 2012 Elsevier Inc. All rights reserved.
Keywords:
Mucormycosis
Mucor
Zygomycosis
Hepatic abscess
Fungal abscess
1. Introduction
Mucormycosis is an uncommon infection that may exhibit a
variety of manifestations, particularly in immunocompromised
patients and those with diabetes mellitus. Here we present a case of
hepatic mucormycosis which was treated with medical and surgical
intervention. We also review the literature regarding mucormycetes
infections, hepatic involvement, and hepatic abscesses.
2. Case
A 58-year-old Vietnamese man with a history of acute myeloid
leukemia (AML), chronic hepatitis B infection, and diabetes mellitus
presented with a 4-month history of worsening left upper quadrant
pain, fevers, and nausea. He was diagnosed with AML in late 2009
after a history of myelodysplasia and was evaluated for unmatched
stem cell transplant from an unrelated donor. He initially had an
excellent response to azacitidine, but stopped chemotherapy while he
returned to Vietnam for several months. When he returned to the
USA, he was restarted on azacitidine with the addition of valproic acid,
supplemented by monthly blood transfusions. He was previously
treated with entecavir for hepatitis B, which was stopped 1 month
prior to admission due to lactic acidosis.
☆ Financial support: This report was unfunded.
⁎ Corresponding author. Tel.: +916-734-3741; fax: +916-734-7766.
E-mail address: [email protected] (S.H. Cohen).
Five months before admission, the patient developed worsening
abdominal pain. An abdominal computed tomography (CT) showed
hepatospenomegaly. He was started on dexamethasone 4 mg twice
daily for treatment of splenomegaly, with improvement in his
symptoms. His dexamethasone dose was subsequently tapered to
4 mg once daily. Two days before admission, he presented to his
primary care physician complaining of worsening left upper quadrant
pain, fevers, nausea, constipation, and difficulty sleeping. Computed
tomographic imaging of the abdomen and pelvis with contrast
showed a localized left-sided subdiaphragmatic abscess measuring
4.9 × 2.8 × 5.2 cm (Fig. 1).
On admission, the patient had a temperature of 97.2 °F, pulse of
98 beats per minute, blood pressure of 117/71 mmHg, respiratory
rate of 16 per minute, and oxygen saturation of 97% on room air.
He was in no distress. Cardiac and pulmonary exam results were
unremarkable. His abdomen was mildly tender to palpation in the
left upper quadrant. His admission laboratory values included the
following: white blood cell count, 9600 cells/μL; hemoglobin, 10.6 g/
dL; hematocrit, 33.9%; platelet count, 120,000 cells/μL; bicarbonate, 24 mEq/L; creatinine, 1.58 mg/dL; serum glucose, 1033 mg/dL;
hemoglobin A1c, 8.2%; total protein, 7.1 g/dL; albumin, 2.5 g/dL; alkaline phosphatase, 83 U/L; aspartate aminotransferase, 14 U/L; alanine
aminotransferase, 19 U/L; and total bilirubin, 1.1 mg/dL. There were
no periods of neutropenia prior to this admission.
Broad-spectrum antibacterials were started including ciprofloxacin 400 mg iv q12 h, vancomycin 1 g q12 h, and metronidazole
500 mg iv q12 h. On hospital day 2, the patient underwent
ultrasound-guided percutaneous pigtail catheter placement with
aspiration of 45 mL of blood-tinged pus. Gram-stain showed
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doi:10.1016/j.diagmicrobio.2012.02.021
Please cite this article as: Henry Su, et al., Hepatic mucormycosis with abscess formation, Diagn Microbiol Infect Dis (2012), doi:10.1016/
j.diagmicrobio.2012.02.021
2
H. Su et al. / Diagnostic Microbiology and Infectious Disease xxx (2012) xxx–xxx
Fig. 1. Hepatic abscess with contiguous spread to the inferior diaphragmatic surface.
numerous white blood cells, but no organisms. Cultures from the
aspirate grew Mucor species.
Antifungal treatment was started with liposomal amphotericin
5 mg/kg every 24 h and micafungin 150 mg iv daily. Broad-spectrum
antimicrobials were discontinued. Repeat abdominal CT 1 week later
showed no resolution of his abscess, and he subsequently underwent left lateral hepatic segmentectomy and resection of a portion
of the left hemidiaphragm. No pleural involvement was observed.
Intraoperative cultures also confirmed the presence of a mucormycetes infection, and surgical margins returned positive for fungal
hyphae. A postoperative CT of the abdomen 3 days after the surgery
showed resolution of the abscess and no pulmonary involvement. A
repeat abdominal ultrasound several days later confirmed the
absence of any well-organized abscess.
The patient clinically improved and was discharged on postoperative day 8. He was continued on daily liposomal amphotericin B for a
planned 6-week course. Micafungin was discontinued, and he was
started on oral posaconazole 400 mg bid. His dexamethasone was
switched to prednisone, and he was discharged on a prednisone taper.
Five days after discharge he returned to the emergency department
with abdominal pain and was found to have abdominal bleeding
requiring emergent exploratory laparotomy which revealed a large
hematoma and diffuse bleeding from the omentum and diaphragmatic surface. Intraoperative tissue samples were negative for the
presence of fungal organisms by both histopathology and culture. He
subsequently had a lengthy hospital stay complicated by Klebsiella
pneumoniae and methicillin-resistant Staphylococcus aureus bacteremia and septic shock requiring intensive care unit admission. The
patient died approximately 2 months after his initial admission.
3. Discussion
Mucormycetes (formerly zygomycetes) responsible for human
disease (in decreasing frequency) include the genera Rhizopus,
Lichtheimia (formerly Absidia), Apophysomyces, Cunninghamella, Saksenaea, Rhizomucor, and Mucor (Alvarez et al., 2009). These pathogens
are distributed worldwide and can be acquired through inhalation,
ingestion, cutaneous exposure, contamination of wounds, trauma, or
injection (Chayakulkeeree et al., 2006). Mucormycosis is typically
seen in immunocompromised individuals, such as patients with
hematologic malignancy, corticosteroid use, solid organ transplantation, injection drug use, AIDS, diabetes mellitus, deferoxamine
therapy, and metabolic acidosis (Chayakulkeeree et al., 2006; Roden
et al., 2005). The most frequent sites of infection are rhinocerebral,
followed by pulmonary, disseminated, gastrointestinal, or cutaneous
(Ribes et al., 2000). Our patient had several risk factors for
mucormycosis, including diabetes mellitus, leukemia, corticosteroid
use, and chemotherapy treatment. The mechanism of transmission in
this case is unknown, although it is most likely that the source was
gastrointestinal with local extension into the liver, since there was
no evidence of a pulmonary source of infection on surgical intervention or radiographic imaging.
The development of improved chemotherapies for hematologic
malignancies has led to an increase in the number of hepatic abscesses
caused by all fungi. Aggressive chemotherapy for hematologic
malignancies, aggressive treatment of malignant hepatobiliary disease, long-term indwelling catheters, prolonged use of broadspectrum antibiotics, long hospitalizations, and use of parenteral
nutritional support have all been associated with fungal abscesses
(Lipsett et al., 1997). The most common species responsible for fungal
abscess formation is Candida albicans, while Aspergillus and Cryptococcus are less commonly identified (Marcus et al., 1993).
Hepatic involvement of mucormycosis is rare and is usually
thought to arise from gastrointestinal disease, although dissemination uncommonly occurs from other sources (Chayakulkeeree et al.,
2006). Hepatic mucormycosis has also been associated with direct
ingestion of naturopathic medicine containing Mucor spp. and is well
documented among neonatal patients (Al-Asiri et al., 1996; Luer
et al., 2009; Oliver et al., 1996). No clear risk factor for hepatic
involvement has been seen, with documented infection observed
among patients with diabetes (Tsaousis et al., 2000), those receiving
chemotherapy for leukemia (Suh et al., 2000), those undergoing
bone marrow transplantation (Oliver et al., 1996; Padmanabhan
et al., 2007), or those with immunosuppression following solid
organ transplantation (Mazza et al., 1999). While most cases occur
in immunocompromised patients, there is 1 documented case of a
patient with both adrenal and hepatic mucormycosis who was
immunocompetent (Li et al., 2010).
Fungal liver abscesses present in similar fashion to bacterial
abscesses, with diffuse abdominal tenderness, jaundice, hepatomegaly, and liver function test abnormalities being the most commonly
observed findings (Marcus et al., 1993).
Of note, fungal hepatic abscesses may occur as mixed fungal/
bacterial abscesses, although these are more commonly seen in
biliary or pancreatic malignancy, whereas pure fungal abscesses are
almost always seen in patients being treated for hematologic
malignancy. The presence of fungemia in the setting of fungal hepatic
abscess is a poor prognostic factor with overall mortality approaching
80% in 1 case series (Lipsett et al., 1997). Regardless of the microbiologic cause, management of hepatic abscess involves drainage and
appropriate antimicrobial therapy.
Hepatic mucormycosis is readily seen on abdominal imaging.
Typical CT findings include the presence of hypodense hepatic lesions
surrounding vessels without a mass effect, representing areas of
liver necrosis due to fungal thrombosis. These findings are not specific but suggest the presence of an angioinvasive organism (Hagspiel
et al., 1995). The presence of a discrete abscess on imaging differs
substantially from radiographic findings of hepatic mucormycosis
previously reported.
The management of mucormycosis consists of 3 key strategies: 1)
rapid initiation of effective antifungal therapy, 2) surgical debridement, and 3) attempts to control predisposing factors, when feasible
(Kontoyiannis and Lewis, 2011). Initial medical therapy for mucormycosis consists of either amphotericin B deoxycholate or lipid
formulations of amphotericin B. The lipid formulations are less
nephrotoxic than amphotericin B deoxycholate and can be safely
administered at higher doses for longer periods (Spellberg et al.,
2005). Echinocandins, such as caspofungin, meanwhile, are not used
as a monotherapy. However, in 1 retrospective study, the combination of amphotericin B lipid complex plus caspofungin was associated with improved outcomes compared to treatment with
amphotericin B lipid complex alone, suggesting that echinocandins
Please cite this article as: Henry Su, et al., Hepatic mucormycosis with abscess formation, Diagn Microbiol Infect Dis (2012), doi:10.1016/
j.diagmicrobio.2012.02.021
H. Su et al. / Diagnostic Microbiology and Infectious Disease xxx (2012) xxx–xxx
may have a synergistic effect with amphotericin B potentially
through an indirect mechanism (Reed et al., 2008). This indirect
immunopharmacologic effect is believed secondary to the unmasking of cell-wall β-D-glucan with subsequent enhanced immune
recognition. This synergistic effect with amphotericin B has also
been observed with the other echinocandins, micafungin and
anidulafungin, as well (Ibrahim et al., 2008a).
The link between iron availability and the risk of mucormycosis is
well known. The predisposition of patients with diabetic ketoacidosis
to mucormycosis is caused in part by the increased availability of iron
during periods of acidemia (Boelaert et al., 1993; Ibrahim et al.,
2008b). Additionally, deferoxamine acts as a siderophore delivering
available iron directly to the fungus (Boelaert et al., 1993). These
findings have prompted interest in the use of other iron chelators
such as deferasirox and deferiprone, neither of which supplies iron
to the Mucorales and which are fungicidal in vitro (Ibrahim et al.,
2007). Chelation therapy was considered in our patient; however,
limited data regarding the efficacy of these agents exist—and a
recently completed randomized, double-blind, placebo-controlled
trial demonstrated a higher mortality in patients treated with deferasirox (Spellberg et al., 2012).
Azole therapy with oral posaconazole has been shown effective
in patients who have failed or cannot tolerate amphotericin B
(Greenberg et al., 2006; van Burik et al., 2006). Some authors recommend amphotericin B and echinocandins in combination for the first
3 weeks of therapy, followed by transition to oral posaconazole as
maintenance/secondary prophylaxis with serial monitoring of
posaconazole serial drug concentrations to monitor compliance
and absorption (Kontoyiannis and Lewis, 2011). Voriconazole
prophylaxis in stem cell transplantation has been associated with
an increased incidence of invasive mucormycosis (Spellberg et al.,
2005). Our patient had never received antifungal prophylaxis with
voriconazole during his courses of chemotherapy.
In conclusion, hepatic mucormycosis is rare and typically seen in
disseminated disease in immunocompromised individuals. Management involves appropriate surgical intervention and medical treatment with intravenous amphotericin B in combination with an
echinocandin, followed by long-term oral posaconazole.
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Please cite this article as: Henry Su, et al., Hepatic mucormycosis with abscess formation, Diagn Microbiol Infect Dis (2012), doi:10.1016/
j.diagmicrobio.2012.02.021