Antimicrobial Agents and Chemotherapy, January 1999, p. 152-156, Vol. 43, No. 1
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Pharmacokinetics of Quinupristin-Dalfopristin in
Continuous Ambulatory Peritoneal Dialysis Patients
Curtis A.
Johnson,1,2,*
Claude A.
Taylor III,3
Stephen W.
Zimmerman,2
William E.
Bridson,2,4
Paul
Chevalier,5
Olivier
Pasquier,5 and
Robert I.
Baybutt5
School of Pharmacy1
and
Medical School,2 University of
Wisconsin, and
Corning Besselaar Clinical Research Unit,
Inc. (Covance Clinical Research Unit, Inc.),4
Madison, Wisconsin;
Cooperative Pharmacy Program,
University of Texas
Austin, Austin, and University of Texas-El
Paso, El Paso, Texas3; and
Rhône-Poulenc Rorer Research and Development,
Collegeville, Pennsylvania5
Received 5 June 1998/Returned for modification 5 September
1998/Accepted 20 October 1998
 |
ABSTRACT |
Quinupristin-dalfopristin may be useful for treatment of organisms
causing peritoneal dialysis-related peritonitis, including methicillin-resistant coagulase-negative staphylococci,
methicillin-resistant Staphylococcus aureus, and
vancomycin-resistant enterococci. The pharmacokinetic profiles of
single intravenous doses of this combination streptogramin antibiotic
of 7.5 mg/kg of body weight were characterized for eight noninfected
patients receiving continuous ambulatory peritoneal dialysis.
Comparison was made to pharmacokinetic profiles determined for
eight healthy volunteers matched by age, sex, and race. Drug was
measured in dialysate up to 6 h following the dose. Plasma and
dialysate were assayed for parent compounds and metabolites. Mean
pharmacokinetic parameters were compared between groups. No
statistically significant differences were observed between groups for
maximal concentrations in plasma, times to maximal concentration, areas
under the curve, distribution volumes, rates of total body clearance,
or half-lives in plasma for quinupristin and dalfopristin. No
statistically significant differences were observed in maximal
concentrations in plasma, times to maximal concentration, areas under
the curve, or half-lives for cysteine, the glutathione conjugates
of quinupristin, or the pristinamycin IIA metabolite of
dalfopristin. The measurements in dialysate of the parent and most
metabolites were below the expected MICs. Dialysis clearance was
insignificant. Quinupristin-dalfopristin was well tolerated in both
groups, causing only mild adverse events that resolved prior to
discharge from the study. The disposition of quinupristin,
dalfopristin, or their primary metabolites following a single dose was
unaltered in patients receiving peritoneal dialysis. Intravenous dosing
of this antibiotic combination is unlikely to be adequate for the
treatment of peritonitis associated with peritoneal dialysis.
| |
INTRODUCTION |
Antibiotic use continues to be
common for patients receiving peritoneal dialysis. Peritonitis
and catheter-related infections are frequent complications of this
dialysis modality. Concerns over the emergence of methicillin-
and vancomycin-resistant microorganisms have led to recent changes in
treatment recommendations for these infections (6).
Methicillin-resistant strains of Staphylococcus aureus
and coagulase-negative staphylococci have been identified for
many years in peritoneal dialysis patients. More recently, vancomycin-resistant Enterococcus faecium and a strain of
S. aureus with intermediate susceptibility to vancomycin
have been observed in peritoneal dialysis patients (2, 7,
9). In addition, antibiotic-resistant strains are a growing cause
of nosocomial infections (12). Quinupristin-dalfopristin, a
new semisynthetic combination streptogramin, has shown in vitro and in
vivo activities against many bacterial strains, including those with
methicillin and vancomycin resistance (4, 10, 11, 13).
Quinupristin-dalfopristin (Synercid; Rhône-Poulenc Rorer) is the
first injectable streptogramin. It is a combination of two semisynthetic derivatives of pristinamycin I and pristinamycin II in a
fixed 30/70 ratio. The two components act synergistically against
gram-positive organisms by inhibiting bacterial protein synthesis
(1). The combination is usually bactericidal in vitro. The
drug is not active against gram-negative bacilli.
Previous studies of healthy volunteers have been conducted to establish
the pharmacokinetic parameters for quinupristin-dalfopristin. Following
intravenous administration of
14C-quinupristin-dalfopristin, approximately 75%
of the dose of drug-related components was excreted unchanged in the
feces while less than 20% was recovered in the urine (5).
Unchanged quinupristin accounted for 35% of total
radioactivity of the pristinamycin I components excreted in the urine,
and its main metabolite, a cysteine conjugate (RPR 100391), accounted
for 38%. No unchanged dalfopristin was recovered in urine, but its
metabolite pristinamycin IIA (RP 12536) represented 70% of total
radioactivity of the pristinamycin II components excreted in the
urine. RPR 100391 and RP 12536 possess in vitro antibacterial
activities comparable to those of quinupristin and dalfopristin,
respectively. The apparent elimination half-life (t1/2
) of each active compound was
approximately 1.5 h for healthy volunteer subjects (3).
Levels of protein binding of quinupristin and
dalfopristin in healthy subjects were 23 to 32% and 50 to 56%,
respectively (11a). The objectives of the present study were
to characterize the pharmacokinetic profiles of
quinupristin-dalfopristin in patients receiving continuous
ambulatory peritoneal dialysis (CAPD), to determine the rate of
antibiotic excretion into the peritoneal effluent, and to compare the
pharmacokinetic parameters of quinupristin-dalfopristin
in CAPD patients to those observed for healthy volunteers with normal
renal function.
| |
MATERIALS AND METHODS |
Eight noninfected CAPD patients and eight healthy volunteers
matched for sex, race, and age (±5 years) participated in this open-label, matched-control study. All participants were between the
ages of 18 and 75 years, were not pregnant, and were within 25% of
their ideal body weights. All CAPD patients had been receiving CAPD and
had been peritonitis-free for at least 1 month. Patients were excluded
if they smoked or if they had a positive serology result for hepatitis
B, hepatitis C, or human immunodeficiency virus. Concomitant
medications that might have affected hepatic microsomal enzymes were
not allowed for 1 month prior to or during the study. All other
medications routinely prescribed for dialysis patients were continued.
All participants gave written informed consent. We obtained a baseline
medical history and electrocardiogram and performed a physical
examination and routine clinical laboratory testing prior to
administration of the study drug. A clinical evaluation of each
participant was repeated on the day of the study prior to drug
administration and 10 h later upon completion of the study. All
CAPD patients were studied in the General Clinical Research Center at
the University of WisconsinMadison. Healthy volunteers were studied
at the Corning Besselaar Clinical Research Unit, Inc. (Covance Clinical
Research Unit, Inc.) in Madison, Wis.
Quinupristin-dalfopristin was given intravenously as a single dose of
7.5 mg/kg of actual body weight. The drug was administered with an
infusion pump over 60 min in 250 ml of dextrose-5% water. All CAPD
patients were subjected to a 1.5% dextrose dialysis exchange just
prior to the start of drug dosing. The subsequent exchange was
performed 6 h later.
Blood sampling.
Two blood samples (4 ml each) were
withdrawn from the arm opposite that receiving the drug infusion at the
following times: time zero (prior to study drug administration); 15, 30, 60, 70, 80, 90, and 105 min after the start of infusion; and 2, 2.5, 3, 4, 5, 6, 8, and 10 h after the start of the infusion.
Samples were withdrawn into two vacuum tubes, each of which
contained 0.5 ml of 3.8% citrate. Immediately after collection,
9 ml of citrated blood was transferred into a tube containing 2 ml of 0.25 N hydrochloric acid kept on ice. The mixture was stirred gently by
hand, and the tube was centrifuged immediately at 2,000 × g and 4°C for 15 min. The resulting plasma supernatants were stored at 
20°C.
Dialysate sampling.
Dialysate effluent (50 ml) was withdrawn
through the peritoneal dialysis catheter at 1.25, 2, 3, and 6 h
following the start of the quinupristin-dalfopristin
infusion. Buffer solution (5 ml, pH 3) was added immediately. Samples
were stored at 20°C.
Sample analysis.
Concentrations of quinupristin
and its metabolites RPR 100391 (cysteine conjugate) and RP 69012 (glutathione conjugate) and of dalfopristin and its metabolite RP 12536 (pristinamycin IIA) in plasma and dialysate were determined by a
specific and sensitive high-performance liquid chromatography method
with UV and fluorescence detection after liquid-solid extraction
(8). With plasma, the assay was linear from a limit of
quantitation of 0.025 to 5 µg/ml for quinupristin,
dalfopristin, and RP 12536 and a limit of quantitation of 0.01 to 1 µg/ml for RP 69012 and RPR 100391, with a 1.35-ml sample volume. With
dialysate, the assay was linear from a limit of quantitation of 0.2 to
2 µg/ml for quinupristin, dalfopristin, and RP 12536 and
a limit of quantitation of 0.01 to 1 µg/ml for RP 69012 and RPR
100391, with a 1.10-ml acidified-dialysate sample volume. Precision and
accuracy of the assay were evaluated by the determination of quality
controls at three different levels (0.2, 1, and 2 µg/ml for
quinupristin, dalfopristin, and RP 12536 and 0.1, 0.5, and
1 µg/ml for RP 69012 and RPR 100391). With plasma, the coefficients
of variation were lower than 11.7% and accuracy was between 96 and
104.8%. With dialysate, the coefficients of variation were lower than
17.7% and accuracy was between 90.7 and 114.3%.
Pharmacokinetic analysis.
Noncompartmental pharmacokinetic
analysis was performed with WinNonlin, version 1.1 (Pharsight of North
Carolina). The maximum concentration of drug in plasma
(Cmax) and the time at which
Cmax occurred (Tmax) were
determined from the experimental concentration-time curve in plasma.
The area under the concentration-time curve (AUC) in plasma from time
zero to the time of the last detectable sample (AUC0-t) was determined by the linear
trapezoidal rule. The AUC in plasma from time zero to infinity
(AUC0-
) was calculated by the trapezoidal rule with
extrapolation to infinity. The rate constant for elimination
(kel) was calculated from the log-linear
regression of the terminal concentration-time data. The apparent
t1/2 was calculated with the equation ln
2/kel. For the metabolites, this apparent
elimination half-life is an aggregate of metabolite formation and
elimination. The clearance (CL) of the parent drugs from plasma was
calculated by dividing the dose by the AUC0-. The
volume of distribution (V) was calculated by dividing the CL
by the kel. Dialysis CL was determined from the
equation
VdCd/AUC0-t,
where Vd is the volume of dialysate,
Cd is the dialysate drug concentration, and
t is the dwell time. CL from plasma and V were
not calculated for the metabolites RP 69012, RPR 100391, and RP 12536.
Statistical analysis.
Mean pharmacokinetic parameters were
compared between groups by t test (parametric) or exact
two-way Wilcoxon rank-sign test (nonparametric) analysis. A
P of <0.05 was considered significant. Pharmacokinetic data
are expressed as means ± standard deviations (SD). Descriptive
statistics were used to summarize the safety evaluation.
| |
RESULTS |
Patient demographics.
The mean age for all participants was
43.6 years (range, 19 to 67 years). The mean weight for the CAPD
patients was 72.2 kg (range, 60 to 104 kg); the mean height for all
participants was 172.2 cm (range, 159 to 182 cm). There were 10 males
(5 in each group) and 6 females (3 in each group). Potential
participants were excluded if they exhibited any evidence of
liver disease. Baseline blood pressures and heart rates were slightly
higher in the CAPD patients and remained so throughout the study.
Pharmacokinetics.
The mean concentration-time profiles in
plasma for quinupristin, RPR 100391, and RP 69012 are
presented in Fig. 1. Quinupristin concentrations could not be determined accurately for CAPD patients 2 and 3 due to suspected interference with furosemide in the plasma. The
mean concentration-time profiles in plasma for dalfopristin and
pristinamycin IIA are presented in Fig.
2. The pharmacokinetic parameters are
presented in Tables 1 and
2. The peak concentrations of all
metabolites in plasma were achieved at nearly the same time as the peak
concentrations of the parent compounds in plasma for both healthy
volunteers and CAPD patients. Mean total CL from plasma for both parent
compounds was high for each group of study participants. There was no
statistically significant decrease in CL from plasma or V
values for the CAPD patients compared to values for the healthy
subjects for either quinupristin or dalfopristin. Moderate
increases in the AUC0-t values for
quinupristin (+18%) and dalfopristin (+29%) were observed
for the CAPD patients compared to those for the healthy volunteers;
however, these differences were not statistically significant. The
AUC0-t values of the metabolites were
comparable in both groups.
Dalfopristin and a glutathione conjugate of quinupristin
(RP 69012) were not detected in dialysis effluent. Quinupristin was detected at very low concentrations (0.24 µg/ml) in the dialysate effluents of only two patients at 1.25 h after the start of the infusion. Pristinamycin IIA was present in dialysate at 1.25, 2, and
3 h after the start of infusion at low concentrations compared to
those observed in plasma. A mean Cmax of 0.207 µg/ml in dialysate was reached at 2 h compared to that of
0.974 µg/ml in plasma at the end of infusion. Dialysate pristinamycin
IIA concentrations at 6 h were nondetectable. The cysteine
conjugate of quinupristin (RPR 100391) appeared slowly in
dialysate, reaching a mean Cmax at 6 h
after the start of infusion. The dialysate RPR 100391 concentrations were low compared to those observed in plasma. RPR 100391 was the only
compound for which peritoneal CL could be calculated (0.56 ± 0.28 liter/h). Peritoneal CL values for quinupristin, dalfopristin, and their respective metabolites were negligible. Due to
the very low rate of dialysate CL for all the compounds, no rate of
appearance of the intravenously administered product into the
peritoneal fluid was estimated.
Safety results.
There were no clinically significant changes
in any of the laboratory parameters from baseline through study
termination 10 h after the start of infusion. There were 34 adverse events, 28 in the CAPD group and 6 in the healthy volunteer
group, as noted in Table 3. All adverse
events were mild, and they resolved prior to discharge from the study.
Six patients and one healthy volunteer experienced pain at the infusion
site. No patients had inflammation at the infusion site, but three of
the healthy volunteers did. Five of the CAPD patients, but none of the
healthy volunteers, experienced nausea.
| |
DISCUSSION |
Previous studies of healthy volunteers have demonstrated that
following a 1-h infusion, quinupristin and dalfopristin
undergo rapid elimination, with t1/2 values
of about 1 h. Approximately 75% of the dose of each compound is
fecally excreted. Less than 20% of the dose is excreted in the urine
as either parent drug or metabolites (5). In a previous
study of intravenous quinupristin-dalfopristin given
to patients with severe chronic renal failure, the disposition profiles
of quinupristin were comparable in patients with
severe renal failure and in healthy volunteers. However, the
elimination of quinupristin metabolites may have been
somewhat impaired, as indicated by selective bioassay. The elimination
of dalfopristin was slightly modified in the renal-failure
patients. The mean Cmax and
AUC0- values for dalfopristin were about 1.3 times
higher than those estimated for healthy volunteers (11a).
For quinupristin and dalfopristin, the results of the
present study are consistent with the results of the earlier study of patients with chronic renal failure. While not statistically
significant, the slight-to-moderate increases in
AUC0-t values in plasma suggest that nonrenal
CL of these compounds may be slightly reduced in patients undergoing
CAPD. The pharmacokinetic parameters for the metabolites in our study
showed some differences compared to those of the earlier study of
chronic renal failure. In the earlier study, statistically significant
increases were observed in the AUC0-t values of
quinupristin and active metabolites, as determined by
bioassay, suggesting an increase of quinupristin metabolite
concentrations. In the present study, no differences in
AUC0-t values for quinupristin metabolites were observed between CAPD patients and healthy volunteers. This difference between the two studies may be explained by differences in analytical techniques used (bioassay versus high-performance liquid
chromatography) or by the contribution of CL via peritoneal dialysis.
This latter hypothesis seems unlikely given the molecular weights of
quinupristin and its metabolites. The pharmacokinetic parameters observed in the present study for the healthy volunteers were similar to those seen in previous studies with volunteer groups.
Patients receiving peritoneal dialysis may develop community-acquired
or nosocomial infections for which
quinupristin-dalfopristin may be indicated. The results of
this study indicate that peritoneal CL of both drugs and their
metabolites is a relatively insignificant contributor to total body CL.
Because insignificant amounts of both parent drugs and their
metabolites are excreted into dialysis effluent, intravenous dosing of
quinupristin and dalfopristin is unlikely to be adequate
for the treatment of peritoneal dialysis-related peritonitis. While the
data from this study suggest that dose adjustments will not be required
for intravenous administration to patients receiving CAPD, future
multiple-dose studies will need to confirm dosing recommendations for
therapeutic use. Currently, there are no data regarding the
intraperitoneal dosing of this antibiotic combination.
| |
ACKNOWLEDGMENTS |
This work was supported by a grant from Rhône-Poulenc Rorer
and in part by NIH grant M01 RR03186 from the National Center for
Research Resources to the University of Wisconsin Medical School.
We thank the following individuals for their invaluable assistance:
Maureen Wakeen, Jim Mroczynski, Linda Lorentzen, Pierre Delplanque,
Abhik Bhattacharya, and the members of the staffs of the University of
Wisconsin General Clinical Research Center and the Corning Besselaar
Clinical Research Unit, Inc. (Covance Clinical Research Unit, Inc.).
| |
FOOTNOTES |
*
Corresponding author. Mailing address: University of
Wisconsin School of Pharmacy, Madison, WI 53706. Phone: (608) 263-5536. Fax: (608) 265-5421. E-mail:
cajohnson{at}pharmacy.wisc.edu.
| |
REFERENCES |
| 1.
| Bouanchaud, D. H. 1992. In-vitro and
in-vivo synergic activity and fractional inhibitory concentration (FIC)
of the components of a semisynthetic streptogramin, RP 59500. J. Antimicrob. Chemother. 30(Suppl.
A):95-99.
|
| 2.
|
Centers for Disease Control and Prevention.
1997.
Staphylococcus aureus with reduced susceptibility to vancomycinUnited States, 1997.
Morbid. Mortal. Weekly Rep.
46:765-766[Medline].
|
| 3.
| Etienne, S. D., G. Montay, A. Le Liboux, A. Frydman, and J. J. Garaud. 1992. A phase I, double-blind,
placebo-controlled study of the tolerance and pharmacokinetic behavior
of RP 59500. J. Antimicrob. Chemother. 30(Suppl.
A):123-131.
|
| 4.
| Finch, R. G. 1996. Antibacterial activity of
quinupristin/dalfopristin. Rationale for clinical use.
Drugs 1(Suppl. 1):31-37.
|
| 5.
|
Gaillard, C.,
J. Van Cantfort,
G. Montay,
D. Piffard,
A. Le Liboux,
S. Etienne,
A. Scheen, and A. Frydman.
1992.
Disposition of the radiolabelled streptogramin RP 59500 in healthy male volunteers, abstr. 1317, p. 330.
In
Program and abstracts of the 32nd Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington, D.C.
|
| 6.
|
Keene, W. F.,
S. R. Alexander,
G. R. Bailie,
E. Boeschoten,
R. Gokal,
T. A. Golper,
C. J. Holmes,
C.-C. Huang,
Y. Kawaguchi,
B. Piraino,
M. Riella,
F. Schaefer, and S. Vas.
1996.
Peritoneal dialysis-related peritonitis treatment recommendations: 1996 update.
Perit. Dial. Int.
16:557-573[Abstract/Free Full Text].
|
| 7.
|
Lai, K. K.
1996.
Treatment of vancomycin-resistant Enterococcus faecium infections.
Arch. Intern. Med.
156:2579-2584[Abstract].
|
| 8.
|
Le Liboux, A.,
O. Pasquier, and G. Montay.
1998.
Simultaneous high-performance liquid chromatographic determination of quinupristin, dalfopristin and their main metabolites in human plasma.
J. Chromatogr. B
708:161-168.
|
| 9.
|
Lynn, W. A.,
E. Clutterbuck,
S. Want,
V. Markides,
S. Lacey,
T. R. Rogers, and J. Cohen.
1994.
Treatment of CAPD-peritonitis due to glycopeptide-resistant Enterococcus faecium with quinupristin/dalfopristin.
Lancet
344:1025-1026[Medline].
|
| 10.
|
Mulazimoglu, L.,
S. D. Drenning, and V. L. Yu.
1996.
In vitro activities of two novel oxazolidinones (U100592 and U100766), a new fluoroquinolone (trovafloxacin), and dalfopristin-quinupristin against Staphylococcus aureus and Staphylococcus epidermidis.
Antimicrob. Agents Chemother.
40:2428-2430[Abstract].
|
| 11.
|
Qadri, S. M.,
Y. Ueno,
F. M. Abu Mostafa, and M. Halim.
1997.
In vitro activity of quinupristin/dalfopristin, RP59500, against gram-positive clinical isolates.
Chemotherapy
43:94-99[Medline].
|
| 11a.
| Rhône-Poulenc Rorer. Data on file.
Rhône-Poulenc Rorer, Collegeville, Pa.
|
| 12.
| Schaberg, D. R., D. H. Culver, and R. P. Gaynes. 1991. Major trends in the microbial etiology of nosocomial
infections. Am. J. Med. 91(Suppl.
3B):72S-75S.
|
| 13.
|
Shonekan, D.,
S. Handwerger, and D. Mildvan.
1997.
Comparative in-vitro activities of RP59500 (quinupristin/dalfopristin), CL 329,998, CL 331,002, trovafloxacin, clinafloxacin, teicoplanin and vancomycin against Gram-positive bacteria.
J. Antimicrob. Chemother.
39:405-409[Abstract/Free Full Text].
|
Antimicrobial Agents and Chemotherapy, January 1999, p. 152-156, Vol. 43, No. 1
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
