Full text of DOI:10.1592/phco.21.7.661.34580

_
B RIEF R EP RTS
Hyperbilirubinemia during Quinupristin-Dalfopristin
Therapy in Liver Transplant Recipients: Correlation with
Available Liver Biopsy Results
Peter K. Linden, M.D., François Bompart, M.D., Sharon Gray, M.S., and George H. Talbot, M.D.
Study Objective. To review the liver histopathology in transplant recipients
who developed hyperbilirubinemia during therapy with quinupristin-
dalfopristin, a new streptogramin antibiotic, and to ascertain whether
objective histologic evidence of adverse drug effect could be correlated to
serum bilirubin levels.
Design. Retrospective analysis.
Setting. University of Pittsburgh Medical Center.
Patients. From a database of 34 liver recipients who received quinupristin-
dalfopristin for vancomycin-resistant Enterococcus faecium infection who
were prospectively enrolled in a multicenter, open-label, emergency-use
protocol, the data for a subset of 25 patients who underwent one or more
liver biopsies during therapy were reviewed for this study.
Interventions. Quinupristin-dalfopristin was administered intravenously at
7.5 mg/kg every 8 hours. Available serum bilirubin levels from before,
during, and 1 week after therapy were tabulated. Liver biopsy results
obtained within 1 week before and during therapy were retrospectively
reviewed. Histopathologic results were characterized and correlated to
bilirubin level.
Measurements and Main Results. Cholestatic changes were already present
in 15 of 17 patients who underwent biopsy before therapy. During therapy,
the most common findings from 40 biopsies (25 patients) were cholestasis
(33 biopsies), acute rejection (10), and periportal inflammation (8). There
was no evidence of drug-specific histopathologic injury.
Conclusion. Hyperbilirubinemia in these patients was likely multifactorial
and most frequently due to sepsis and prior graft injury.
(Pharmacotherapy 2001;21(6):661–668)
strains of bacteria has been rising,1, 2 with
vancomycin-resistant enterococci implicated in
an increasing percentage of nosocomial infections
since the late 1980s. A recent surveillance report
of bloodstream infections in the United States
from 1995–1998 ranked enterococci as the third
most frequent pathogen, with 50% of
Enterococcus faecium strains exhibiting high-level
resistance to vancomycin.3 These infections are a
particular problem in immunocompromised
patients, including liver transplant recipients, for
In recent years, the rate of antibiotic resistance
for many clinically important gram-positive
From the Division of Critical Care Medicine, University
of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (Dr.
Linden), and Aventis Pharmaceuticals, Bridgewater, New
Jersey (Drs. Bompart and Talbot, and Ms. Gray).
Supported by Aventis Pharmaceuticals, Bridgewater, New
Jersey.
Address reprint requests to Peter K. Linden, M.D.,
University of Pittsburgh Medical Center, Division of Critical
Care Medicine, Scaife Hall/Room 602-A, 200 Lothrop Street,
Pittsburgh, PA 15213; e-mail: pkl@med.pitt.edu.

662
PHARMACOTHERAPY Volume 21, Number 6, 2001
whom vancomycin-resistant enterococci are
associated with very high morbidity and
mortality.4–7
sepsis). Informed consent was obtained from
patients or their next of kin. Quinupristin-
dalfopristin was administered at a dosage of 7.5
mg/kg every 8 hours intravenously. The duration
of treatment was clinician-determined, based on
site and severity of infection; the subsequent
clinical course; and follow-up cultures. All
clinical, laboratory, and microbiologic data were
prospectively collected.
The emergence of multidrug-resistant
pathogens has given urgency to the development
of new antimicrobials with the potential for
activity against these organisms. One such agent
is quinupristin-dalfopristin (Synercid; Aventis
Pharmaceuticals, Bridgewater, NJ), a strep-
togramin active against most gram-positive
organisms. Quinupristin-dalfopristin is active
against staphylococci, including methicillin-
resistant strains; streptococci, including
penicillin-resistant strains; and E. faecium,
including those with high-level glycopeptide
resistance.8–11
Conjugated hyperbilirubinemia was reported
in phase III clinical trials of quinupristin-
dalfopristin, although this was in the absence of
any prospective histopathologic (liver biopsy)
investigation.12 Data from phase III comparative
and noncomparative trials with quinupristin-
dalfopristin did not demonstrate significant
elevations of either hepatic transaminase
(aspartate aminotransferase, alanine amino-
transferase) levels or alterations in liver synthetic
function tests (serum albumin level or
prothrombin time).
Liver transplant recipients with serious or life-
threatening infection due to vancomycin-
resistant enterococci have received quinupristin-
dalfopristin therapy on an emergency-use basis.
The elevation of serum bilirubin level is a
common laboratory finding in liver transplant
recipients, particularly in the setting of
concomitant critical illness.13 In this complex
population, hyperbilirubinemia may be due to
single or multiple factors.
Liver Transplant Protocol and Monitoring of
Liver Function
Liver recipients routinely received immuno-
suppressive therapy with intravenous or oral
tacrolimus adjusted on the basis of daily serum
trough levels, and with either intravenous
methylprednisolone or oral prednisone. Liver-
associated enzymes (alanine aminotransferase,
gamma glutamyl transferase) and serum bilirubin
levels generally were obtained every 1–2 days in
critically ill liver transplant recipients, as a means
of monitoring for allograft rejection while the
patient received reduced levels of immuno-
suppressive therapy. Liver biopsies were
performed for unexplained and clinically
important elevations in liver-associated enzyme
levels and were performed either by percutaneous
aspiration or directly at the time of laparotomy.
Histopathologic examination of liver tissue was
performed with hematoxylin and eosin stain,
silver stain, and a variety of other special stains
based on the individual case.
Data Retrieval and Organization
Demographic, clinical, microbiologic, and
laboratory data for all quinupristin-dalfopristin
recipients treated at the University of Pittsburgh
Medical Center were prospectively entered into a
computerized database (Paradox; Borland, Scotts
Valley, CA). The subset of liver transplant
recipients for the present analysis was retrieved
from this database. The available serum bilirubin
levels from 3 days before, during, and 1 week
after quinupristin-dalfopristin therapy were
tabulated. The results from all liver biopsies
performed during the corresponding periods
were obtained from the computerized medical
archive at the University of Pittsburgh Medical
Center.
Methods
Subjects
Patients with serious infection due to
vancomycin-resistant E. faecium (VREF) were
prospectively enrolled at the University of
Pittsburgh Medical Center in an institutional
review board-approved, multicenter, open-label,
emergency-use protocol during a 22-month
period (January 1995–October 1996). Eligibility
criteria were the following: isolation of VREF
from a clinically important site (blood, urine,
abscess, wound), in vitro resistance to other
appropriate conventional antimicrobials, and
concomitant signs and symptoms of systemic
and/or local infection (e.g., fever, leukocytosis,
Data Analysis
Individual and total sample median bilirubin
levels were recorded for the first day of

LIVER HISTOPATHOLOGY DURING QUINUPRISTIN-DALFOPRISTIN THERAPY Linden et al 663
Table 1. Characteristics of 25 Liver Transplant Recipients
Who Received Quinupristin-Dalfopristin Therapy for
Vancomycin-Resistant Enterococcus faecium Infection
16 days (range 7–463 days). In all patients, the
abdomen was the primary site of E. faecium
infection, manifested as follows: diffuse
Characteristic
Transplant Recipients
peritonitis (16 patients), an intraperitoneal fluid
collection (5), cholangitis (2), and deep wound
infection (2). Bacteremia was present in 18
(72%) of the 25 patients. A pathogen(s) other
than VREF was present at the primary abdominal
site in 18 patients. The most common non-VREF
pathogens were facultative gram-negative bacilli
(8 patients), Pseudomonas aeruginosa (4),
anaerobes (3), coagulase-negative staphylococci
(2), Staphylococcus aureus (4), and Candida sp
(3). The majority of patients exhibited one or
more major organ system failures, including
shock (18 patients), acute renal failure requiring
hemodialysis (18), or respiratory failure
requiring mechanical ventilation (21).
Median age (range), yrs
M/F
Primary liver disease
Hepatitis C
Ethanol abuse
Cryptogenic
Sclerosing cholangitis
Primary biliary cirrhosis
Median (range) posttransplantation
interval, days
Prior liver transplantation
Intraabdominal infection
Bacteremia
Admitted to intensive care unit
Shock
Renal failure
52 (28–68)
19/6
14
6
2
2
1
16 (7–463)
5
25
18
24
18
18
21
Mechanical ventilation
Quinupristin-Dalfopristin and Other Therapies
Quinupristin-dalfopristin was administered
intravenously at 7.5 mg/kg every 8 hours in all
patients, without subsequent dose adjustment.
The median duration of therapy was 13 days
(range 6–36 days). Twenty-two patients received
one or more other antimicrobials during the
follow-up period. The five most frequently
administered agents were ceftazidime (14
patients), piperacillin (12), vancomycin (10),
metronidazole (9), and amphotericin B (8).
Sixteen patients underwent one or more surgical
interventions during the period of quinupristin-
dalfopristin therapy, primarily for abdominal
drainage or debridement (12 patients) and
surgical reconstruction of the hepatic artery (2)
or biliary duct (2). Eighteen patients also
received total parenteral nutrition during all or
part of the quinupristin-dalfopristin therapy
period.
quinupristin-dalfopristin therapy and at peak
level during therapy. All available histopathologic
results were characterized and correlated to the
bilirubin level.
Results
A total of 44 patients with a serious infection
caused by VREF received quinupristin-
dalfopristin during the 22-month study period.
Thirty-four patients (77%) were liver transplant
recipients. These liver transplant recipients
received quinupristin-dalfopristin for a median
duration of 13 days (range 6–36 days). Twenty-
five of the 34 liver recipients underwent one or
more (range 1–5) liver biopsies during therapy
with quinupristin-dalfopristin; thus, these 25
composed our study cohort. Seventeen of these
25 liver recipients also underwent liver biopsy
less than 1 week before quinupristin-dalfopristin
therapy was initiated, providing a baseline for
any subsequent histopathologic hepatic changes.
Serum Bilirubin Levels at Baseline and during
Quinupristin-Dalfopristin Therapy
The frequency distribution of baseline total
serum bilirubin levels on the first day of
quinupristin-dalfopristin therapy is shown in
Figure 1. The median serum bilirubin level was
6.1 mg/dl, with a wide range of 0.6–35.7 mg/dl
(normal reference range 0.1–1.2 mg/dl).
Conjugated (direct) levels were obtained in only
Clinical and Microbiologic Characteristics
The clinical and microbiologic characteristics
of the 25 liver recipients are illustrated in Table
1. Twenty patients were first-time liver
recipients, whereas five patients already had
undergone a second liver transplantation due to
prior liver graft failure. The most common
causes of pretransplantation liver disease were
hepatitis C (14 patients) and ethanol abuse (6).
The median posttransplantation interval on the
first day of quinupristin-dalfopristin therapy was
eight patients.
The mean conjugated
bilirubin:total bilirubin ratio in this subset was
0.85 (0.7–1.0). The trend in bilirubin level from
3 days before quinupristin-dalfopristin therapy to
baseline was already increasing at least 1 mg/dl in

664
PHARMACOTHERAPY Volume 21, Number 6, 2001
Table 2. Serum Bilirubin Trends and Timing of Peak Bilirubin Level and
Liver Biopsies in 25 Liver Transplant Recipients during Quinupristin-
Dalfopristin Therapy
Patient
No.
Serum Bilirubin Level (mg/dl)
Therapy Day of
Liver Biopsya
Baseline
Peak (therapy day)
1
2
0.6
6.1
6.3 (15)
6.1 (1)
14
20
3
4
5
6
7
8
21.4
1.7
6.1
14.9
15.5
4.6
35.4 (4)
19.4 (10)
11.6 (8)
20.0 (12)
19.4 (7)
9.7 (6)
6, 8
9
3
5, 7
3
7
9
35.7
6.0
5.5
25.9
1.1
4.9
12.2
4.5
3.4
5.0
18.2
1.6
8.6
11.5
2.2
23.0
5.3
45.0 (11)
30.8 (14)
25.1 (16)
38.5 (7)
1.9 (12)
13.0 (16)
26.6 (12)
5.3 (10)
24.2 (18)
7.5 (18)
22.7 (7)
3.1 (8)
19.1 (6)
19.2 (12)
3.7 (9)
23.0 (1)
26.2 (11)
9
9
11
7
10
7, 11, 14
7, 10
8
8, 11, 15
6, 10
7
7
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
3, 5
7, 13, 18, 26, 33
5, 8, 15
20
5
aNine patients underwent 2 or more (range 2–5) biopsies.
14 patients, decreasing at least 1 mg/dl in 7
patients, and remaining stable (change < 1 mg/dl)
in 4 patients. During quinupristin-dalfopristin
therapy, the median peak bilirubin level was 19.4
mg/dl (range 1.9–45.0 mg/dl). Table 2 summarizes
the trends in serum bilirubin levels from baseline
to peak level for all 25 patients during
quinupristin-dalfopristin therapy. Two patients
(patients 1 and 13) had a normal baseline
bilirubin level that increased during therapy, and
in another two patients (patients 2 and 24) the
peak level occurred at baseline and subsequently
decreased during therapy. The most commonly
observed pattern (21 patients) was an elevated
baseline level that increased during quinupristin-
dalfopristin therapy.
Liver Biopsy Results
Cholestatic changes were already present in 15
of the 17 patients who underwent liver biopsy
within 7 days before beginning quinupristin-
dalfopristin therapy. The cholestatic changes
were attributable to ischemic preservation injury
and sepsis that was already established. Biliary
outflow obstruction subsequently was ruled out
by cholangiography and/or ultrasonography in
seven patients. Other histologic findings were
mild to moderate cellular rejection (4 patients),
steatosis (3), fibrosis (1), and cytomegalovirus
hepatitis (1).
Findings from 40 liver biopsies performed
during quinupristin-dalfopristin therapy were
Figure 1. Serum bilirubin levels on first day of
quinupristin-dalfopristin therapy.

LIVER HISTOPATHOLOGY DURING QUINUPRISTIN-DALFOPRISTIN THERAPY Linden et al 665
Table 3. Comparison of Liver Biopsy Results 7 Days before and during
Quinupristin-Dalfopristin Therapy
Before Therapy
(n=17)
During Therapy
(n=25)
Histologic Finding
Cholestasis
Rejection
Periportal inflammation
Fibrosis or necrosis
15
4
0
25
10
8
1
6
Noneosinophilic lobular inflammation
Steatosis
Cytomegalovirus hepatitis
0
3
1
4
3
3
Data are number of patients.
available in the 25 patients (range 1–5
biopsies/patient). The most common findings
during therapy were cholestasis with
cholangiolar proliferation and/or bile duct
plugging, which was present in all 25 patients
and at multiple biopsies (2–5 biopsies) in 8
patients. Periportal inflammation was seen in 8
patients (11 biopsies) and consisted of a mixed
cell population of lymphocytes and polymorpho-
nuclear leukocytes. Other histologic findings in
order of decreasing frequency were acute
rejection (10 patients), necrosis or fibrosis (6),
noneosinophilic lobular inflammation (4),
macrovesicular steatosis (3), and cytomegalo-
virus infection (3). Notably, no evidence was
found of eosinophilic infiltration, granuloma
formation, or other more specific drug-related
histologic changes in any liver biopsy specimen
obtained during quinupristin-dalfopristin
therapy. Table 3 shows a comparison of the
histologic findings obtained before and during
quinupristin-dalfopristin therapy.
attributable cause. For the eight patients, the
median peak serum bilirubin level during
therapy was 6.2 mg/dl, and the posttherapy
median serum bilirubin level at last in-hospital
day was 3.0 mg/dl.
Discussion
Our series included a very ill and complex liver
transplant recipient population with
intraabdominal sepsis due to VREF, in whom we
observed a rise in bilirubin levels during
treatment with the parenteral streptogramin,
quinupristin-dalfopristin. All were liver
recipients at the same transplant center who
underwent immunosuppression with cortico-
steroids and tacrolimus, exhibited intraabdominal
VREF infection or sepsis, and were treated with
the same dosage of quinupristin-dalfopristin.
Hyperbilirubinemia was reported in 3.1% of
patients who received quinupristin-dalfopristin
versus 1.3% of patients treated with comparator
agents.14 These patients included both liver
transplant recipients and patients who had not
undergone prior liver transplantation. It is
unknown whether the incidence and magnitude
of hyperbilirubinemia is greater in liver recipients
than in other patients who receive treatment with
quinupristin-dalfopristin. Our study population
was skewed as we selected only septic liver
recipients whose elevated liver enzyme levels
prompted one or multiple liver biopsies. The
incidence of hyperbilirubinemia may indeed be
higher in such patients; however, this
noncontrolled, retrospective series was not
designed to answer this question.
Clinical Outcome and Posttherapy Bilirubin
Trend
Sixteen (64%) of the 25 analyzed liver
transplant recipients died of multisystem organ
failure during quinupristin-dalfopristin therapy.
In eight of the remaining nine patients, follow-up
bilirubin levels were measured after the elective
discontinuation of quinupristin-dalfopristin, for a
median in-hospital follow-up of 17 days (range
3–116 days). The eight patients with posttherapy
follow-up were discharged from the hospital. In
five of these patients, the serum bilirubin level
decreased from the peak level during therapy to a
normal or near-normal level when measured at
the last in-hospital day. In the three other
patients, however, the bilirubin level increased in
the follow-up period. In two of these patients,
thrombosis of the hepatic artery was the
Prior reports of elevated bilirubin levels refer to
the conjugated fraction.15 Since conjugated
bilirubin levels were only sporadically obtained
in this series, most of this report focuses on total
bilirubin levels. In the absence of accelerated red
blood cell destruction (i.e., hemolysis), the total

666
PHARMACOTHERAPY Volume 21, Number 6, 2001
bilirubin level closely reflects the conjugated
level in the liver recipient.
the initiation of quinupristin-dalfopristin therapy,
coupled with the persistence of preexistent or de
novo cholestasis, could reflect the effects of
sepsis, ischemia, or parenteral nutrition and/or a
superimposed drug effect. The available
histopathologic data did not demonstrate
unexplained eosinophilic infiltration or
granulomatous changes, which were described in
some drug-induced hepatic reactions. As
expected, the liver biopsies performed during
quinupristin-dalfopristin therapy showed
predominantly cholestatic and other degenerative
changes, rejection, and cytomegalovirus
infection. The six biopsies (in four patients) that
showed hepatocyte-lobular inflammatory
changes were due exclusively to polymorpho-
nuclear cells and lymphocytes and most likely
represented an early recurrence of hepatitis C in
the liver allograft, on the basis of their
pretransplantation history of chronic hepatitis C
and serologic evidence of active hepatitis C
replication. The normalization in serum
bilirubin levels in five of the eight patients with
posttherapy follow-up may reflect a diminution
of the cholestatic effects due to quinupristin-
dalfopristin and/or improvement in the septic
condition of the patients.
There is ample precedent for the association of
systemic antimicrobial administration and
adverse effects on both liver function and
histology. Such reports have documented a
diverse clinical presentation that includes frank
hepatitis with or without necrosis, granulomatous
disease, cholestasis, steatosis, cholelithiasis, and
pseudolithiasis.26, 27 Cholestatic disease was
associated with amoxicillin-clavulanate,28, 29
ticarcillin-clavulanate,30 mezlocillin,31 the
antistaphylococcal penicillins (flucloxacillin,
cloxacillin, dicloxacillin, oxacillin, and
nafcillin),32–35 tetracycline,36 imipenem-
cilastatin,37 and others. Within the macrolide-
lincosamide-streptogramin family, there are also
important and similar case descriptions. Most
frequently these have been erythromycin-
estolate,38 but also erythromycin ethylsuccinate,39, 40
erythromycin stearate,38 erythromycin pro-
pionate,41 and erythromycin-base42 derivatives,
which produce an idiosyncratic hypersensitivity
reaction manifesting as cholestatic hepatitis.
Other macrolide-lincosamide-streptogramin
agents associated with intrahepatic cholestasis
include clindamycin,43 midecamycin,44 spiramycin,45
and azithromycin.46
The frequent performance of liver biopsy in
these patients provided an opportunity to look
for potential quinupristin-dalfopristin–related
histopathologic effects. In 21 (84%) of the 25
patients in our study, the serum bilirubin level
was already elevated before quinupristin-
dalfopristin therapy and continued to rise further
during therapy.
The serum bilirubin level reflects a complex
metabolic and anatomic sequence that includes
hemoglobin breakdown from senescent
erythrocytes, hepatic uptake at the sinusoidal
membrane, and active secretion at the canalicular
membrane of both inorganic and organic
compounds that together constitute bile.
Elevation of the conjugated (direct) bilirubin
fraction points to abnormalities in the
postsinusoidal sequence due to either intra- or
extrahepatic influences. The dominant histologic
finding in the 17 patients with baseline liver
biopsies was a variable degree of intrahepatic
cholestasis. Cholestasis is a stereotypical
histologic response to a variety of biologic
processes including sepsis,16 total parenteral
nutrition,17 drugs,18 and in liver transplant
recipients, biliary duct cell injury due to ischemic
preservation of the donor liver that carries over
into the posttransplantation period.19 Inhibition
of bile acid transport has been reproduced by
endotoxin administration to both isolated
perfused liver and isolated basolateral sinusoidal
and canalicular membrane vesicle models.20 Both
tumor necrosis factor (TNF)-␣ and interleukin-6
have inhibited the formation and secretion of bile
acids in other models, and anti-TNF antibodies
have reversed endotoxin-induced reductions in
bile flow.21–23
Another study24 demonstrated that hyper-
bilirubinemia was a marker for poor prognosis in
S. aureus sepsis and that hepatic excretory
function was impaired in rabbits challenged with
either S. aureus isolates or lipoteichoic acid from
human blood. A prior study has shown that
endotoxin may play a role in the pathogenesis of
total parenteral nutrition-induced jaundice and
that enhanced TNF-␣ production may produce
the cholestasis observed in ischemia reperfusion
injury in orthotopic-liver recipients.25 Thus, one
or multiple factors may have produced
hyperbilirubinemia and biopsy evidence of
cholestasis before the administration of
quinupristin-dalfopristin.
With regard to quinupristin-dalfopristin,
conjugated hyperbilirubinemia was not observed
The further rise in serum bilirubin levels after

LIVER HISTOPATHOLOGY DURING QUINUPRISTIN-DALFOPRISTIN THERAPY Linden et al 667
after its administration to healthy human
volunteers but was seen in quinupristin-
dalfopristin–treated patients in phase III
studies.12 Elevations of conjugated bilirubin
levels greater than five times the upper limit of
normal occurred in 5.5% of quinupristin-
dalfopristin–treated patients compared with 2.1%
of patients receiving comparator antimicrobials
(p=0.0001).12 The difference in elevation of total
bilirubin was less marked (1.5% vs 0.7%,
p=0.0817). An even higher incidence of
hyperbilirubinemia was seen in the non-
comparative emergency-use trial from which the
patients in the current study were derived.47
mechanisms include a “sludging” effect on bile
and/or changes in the bile duct epithelium.
Elevations of serum bilirubin levels from any
cause may have important implications in the
patient receiving quinupristin-dalfopristin. The
quinupristin moiety is transformed in the liver
microsomal system to its water-soluble
glutathione- and cysteine-conjugates, which are
subsequently excreted in the bile.50 The
development of cholestasis and compromised
biliary excretion can lead to the accumulation of
quinupristin metabolites. The relationship, if
any, of underlying liver disease to the
development of the myalgia-arthralgia syndrome
remains unclear.51
The multitude of possible causes for cholestasis
in our patients makes it difficult to assess the
independent contribution of quinupristin-
dalfopristin toward this phenomenon. There are
two distinct histologic categories of drug-induced
liver injury: cytotoxic injury and cholestatic
injury. The former displays diffuse, zonal, or
patchy necrosis and/or steatosis (fatty change)
and is precipitated by many agents including
isoniazid, phenytoin, halothane, and methyldopa.
Cholestatic injury may be accompanied by portal
inflammation (hepatocanalicular type) or may
have little or no portal inflammation (canalicular
or bland type).48 To the extent that quinupristin-
dalfopristin may have caused part of the
histologic findings, both patterns were seen in
our patients. A reduction in number of biliary
ducts (ductopenia) was described with both
drug-induced hepatic injury and chronic allograft
rejection; however, this feature was not observed
in our study. Two common underlying
conditions that may have caused intrahepatic
cholestatic changes in many of our patients were
postpreservation cholestasis due to cold or warm
allograft ischemia in the pre- or peritrans-
plantation periods and intraabdominal sepsis. In
such complex patients in whom cholestasis may
be uni- or multifactorial, a close examination of
the patient’s recent drug exposure and underlying
medical condition is critical to establishing the
most likely cause(s). The definite mechanism of
elevated conjugated bilirubin due to
quinupristin-dalfopristin is still unknown. It is
possible that quinupristin-dalfopristin may
interfere with conjugated bilirubin transport,
perhaps by competitive inhibition of the
canalicular multiple organic anion transport
protein, as can occur with other antimicrobials
such as ampicillin, ceftriaxone, and rifampin.49–51
This effect may have no specific histologic
marker other than cholestasis. Other possible
Intrahepatic cholestasis, which often appears to
be multifactorial, is a ubiquitous histologic
finding in severely ill liver recipients with serious
VREF infection. Based on lack of drug-specific
histologic injury in our series, the automatic
cessation of quinupristin-dalfopristin therapy for
new-onset or worsening hyperbilirubinemia in
liver transplant recipients does not appear to be
warranted. Decisions to terminate quinupristin-
dalfopristin should be made on a case-by-case
basis.
As is the situation with many
antimicrobials that undergo hepatic metabolism,
there are no firm guidelines for dosage
adjustment of quinupristin-dalfopristin based
solely on elevations of serum bilirubin level.
However, in liver transplant recipients, liver
histopathologic examination may direct
appropriate treatment for nondrug-related causes.
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