Download Gram-Positive Resistance: Pathogens, Implications, and Treatment

Gram-Positive Resistance: Pathogens, Implications, and
Treatment Options
Insights From the Society of Infectious Diseases Pharmacists
Ronda L. Akins, Pharm.D.; Krystal K. Haase, Pharm.D.
Pharmacotherapy. 2005;25(7):1001-1010. ©2005 Pharmacotherapy Publications
Posted 07/12/2005
Abstract and Introduction
Abstract
Despite the advent of new antibiotics, resistance in gram-positive pathogens,
including staphylococci and enterococci, continues to increase. This is evident with
the recent emergence of vancomycin-resistant Staphylococcus aureus. Newer
treatment agents are available, including quinupristin-dalfopristin, linezolid, and
daptomycin. In addition, investigational agents are being explored. Clinical trials
have been conducted for various infections, such as skin and skin structure
infections, pneumonia, and bloodstream infections. Antibacterial activity, site of
infection, and potential for adverse effects must be taken into account when
making decisions regarding therapy.
Introduction
Antibiotic resistance is an ongoing problem despite the development of new
therapeutic options. Gram-positive pathogens are of particular concern, as
resistance is increasing in organisms that have been susceptible to most available
antibiotics until the past decade. Vancomycin has remained the gold standard
antibiotic for treatment of resistant gram-positive organisms. However, the
increased frequency of vancomycin-resistant enterococci (VRE) has necessitated
the development of other agents.
Two agents, quinupristin-dalfopristin and linezolid, were previously approved for the
treatment of VRE. Simultaneously, a small number of Staphylococcus aureus
isolates with intermediate resistance to vancomycin emerged worldwide.[1-3]
Concern then turned to the issue of whether S. aureus could become fully resistant
to vancomycin. This fear was realized in 2002, when two clinical isolates of
vancomycin-resistant S. aureus (VRSA) were identified.[4-7] A third isolate of VRSA
was identified in March 2004.[8, 9]
At the end of 2003 a third agent, daptomycin, was approved with an indication for
complicated skin and skin structure infections due to S. aureus (including isolates
with methicillin resistance), streptococci, and vancomycin-susceptible Enterococcus
faecalis.[10] However, in vitro data demonstrating activity for daptomycin against
multidrug-resistant gram-positive organisms led to use of this agent as a viable
treatment alternative to vancomycin, quinupristin-dalfopristin, and linezolid.[11]
Other investigational antibiotics are in the pipeline but are not yet available.
Unfortunately, despite the development of new antibiotics, organisms continue to
demonstrate increasing resistance patterns. Resistance has already been identified
in numerous organisms, including staphylococci and enterococci, for two of the
three agents targeted for use against resistant gram-positive pathogens.
Pathogens
National Nosocomial Infection Surveillance data demonstrate that the frequencies of
methicillin-resistant S. aureus (MRSA), methicillin-resistant S. epidermidis (MRSE),
and VRE isolated from intensive care units were 57.1%, 89.1%, and 27.5%,
respectively, in 2002.[12] The increases in MRSA and VRE exceeded earlier trends
(2002 vs 1997-2001), as the frequency of MRSA increased by 13% and that of VRE
rose by 11%. On the other hand, MRSE increased by only 1% over the same time
period. Another gram-positive organism causing heightened concern is multidrugresistant Streptococcus pneumoniae.
As rates of MRSA have increased to greater than 50% for staphylococcal isolates
identified in most institutions around the United States, the use of vancomycin has
continued to increase. This trend, along with the increased use of other classes of
antibiotics (third-generation cephalosporins and fluoroquinolones) has in turn
affected the resistance rates of other gram-positive organisms, particularly
staphylococci and enterococci.[13, 14]
In 1996, the first isolate of vancomycin intermediate-resistant S. aureus (VISA),
also known as glycopeptide intermediate-resistant S. aureus (GISA), was identified
in Japan.[1, 2] This was followed by reports of multiple cases worldwide, including
eight cases from the United States. Once VISA was identified, concern mounted
that fully vancomycin-resistant S. aureus would develop. This happened in the
United States in 2002, when two cases of VRSA were identified; a third case
followed in March 2004. This development was not due to progression of the
resistance mechanism identified in the VISA strains but to acquisition of the vanA
gene from vancomycin-resistant enterococci. The resistance seen in VISA strains is
due to a thickened cell wall resulting in an increased number of D-ala-D-ala
targets; this alteration prevents adequate drug concentrations from reaching
binding sites before being incorporated into the structure of the cell wall. [15, 16]
In contrast, VRSA resistance is due to plasmid-mediated transfer of the vanA
resistance gene.[7] The first case of VRSA occurred in June 2002 in a patient from
Michigan, the second in a patient in Pennsylvania in September 2002, and the third
in a patient in New York in March 2004.[4-9] The patient in Michigan had a
concurrent VRE infection, whereas the patients in Pennsylvania and New York had
past VRE infections. Molecular typing showed that all VRSA isolates contained the
mecA and vanA genes. The vanA gene was likely transferred to the staphylococcal
isolate from the VRE strain. Reported minimum inhibitory concentrations (MICs) for
these three strains varied significantly: greater than 256 µg/ml for the Michigan
strain versus 64 µg/ml for the Pennsylvania and New York strains.[4-9] All three of
the isolates were susceptible to linezolid, quinupristin-dalfopristin, and
trimethoprim-sulfamethoxazole.[4-9] However, in vitro time-kill studies showed
bacteriostatic activity for both linezolid and quinupristin-dalfopristin against the
Pennsylvania strain.[7] Linezolid was also bacteriostatic against the Michigan
strain.[17] Other in vitro studies have shown the first two VRSA isolates to be
susceptible to other agents, with daptomycin, oritavancin, and dalbavancin having
bactericidal activity and tigecycline having bacteriostatic activity.[7, 17, 18] To our
knowledge, there are no published data regarding other antibiotic susceptibilities to
the New York strain. Each patient had multiple risk factors for resistant infections:
underlying morbidity (diabetes mellitus, renal insufficiency, and morbid obesity),
past infections (chronic infected foot ulcers, chronic urinary tract infections), past
antibiotic exposure, and past hospitalization.
Most MRSA infections have been predominantly nosocomial in origin. However, an
emerging concern with S. aureus is an increase in community-acquired strains with
significantly different susceptibility profiles than the nosocomial strains.
Community-acquired methicillin-resistant S. aureus (CA-MRSA) is encountered
around the world, including North America and Europe, with some areas reporting a
frequency above 20%.[19-23] Most patients with CA-MRSA have skin and skin
structure infections. These infections have been reported worldwide and occur in
persons without any established risk factors, such as recent hospitalization or
antibiotic exposure, dialysis, devices, or comorbid conditions.
Unlike nosocomially acquired MRSA, most CA-MRSA strains remain susceptible to
most antibiotics, except for β-lactams. Vancomycin has greater activity than other
antimicrobials against these community-acquired isolates. After vancomycin, these
pathogens are most susceptible to clindamycin and trimethoprim-sulfamethoxazole,
with 92-100% and 88.9-98% susceptibility, respectively.[24, 25] Although most
isolates are susceptible to clindamycin, it has the potential to develop resistance
secondary to induction of the erm gene. This mechanism of resistance may hinder
its use as a single agent and necessitate its use in combination with other agents.
Minocycline and gentamicin have also shown activity.[24, 25] It is important to note
that regional variations of resistance exist for CA-MRSA.[26] Thus, therapy should be
monitored and appropriately adjusted based on the sensitivity report for a given
patient.
Coagulase-negative S. epidermidis is another organism with significant resistance,
showing methicillin-resistance rates of 80-90%. Although historically recognized as
a contaminant resulting from normal flora, its pathogenicity has been recognized in
patients with impaired immune function. In addition, MRSE is a cause of infection in
patients with implanted prosthetic material or implanted medical devices and in
certain postoperative infections.[27, 28] Many cases of glycopeptide-resistant
coagulase-negative staphylococci have been reported.[29-32] Biofilm formation
appears to play a role in both virulence and antibiotic effectiveness with this
organism.[33, 34]
Frequency of resistance in enterococci has steadily risen over the past decade.
Vancomycin-resistant enterococci have become commonplace in most institutions
throughout the United States. Both enterococcal strains (E. faecium and E. faecalis)
have demonstrated high-level resistance to vancomycin, but most strains of E.
faecalis remain susceptible to vancomycin. Indiscriminate use of antibiotics,
particularly third-generation cephalosporins, has influenced the resistance patterns
now observed in enterococci.[14] Over the past 2 decades (coinciding with
identification of VRE isolates) guidelines have helped slow the continued increase in
resistance.[35] These guidelines have addressed infection control practices and
antibiotic use policies. Despite these efforts, resistance rates continue to rise. Other
factors also exist that increase the likelihood of VRE infections, including impaired
immune function and prolonged hospital stay. It is important to note that positive
cultures for VRE in urine or stool do not represent an active infection but more
likely just colonization. Treatment for these patients is often dependent on clinical
judgment based on signs and symptoms and therefore should not be implemented
based solely on the culture results.
The rate of multidrug-resistant S. pneumoniae is continuing to rise. Resistance to
penicillin is approximately 25% for all isolates in the United States and 30.4% for
meningeal isolates.[36] Although many of these resistant isolates are susceptible to
third-generation cephalosporins, the rate of resistance to these antibiotics has also
increased. The National Committee for Clinical Laboratory Standards (NCCLS) has
identified new breakpoints for cefotaxime and ceftriaxone susceptibilities for S.
pneumoniae for both meningeal and nonmeningeal isolates.[36] Cephalosporin
resistance was 16% for all isolates with the former breakpoints compared with
6.4% with the new breakpoints. In these species, β-lactam resistance is typically
accompanied by resistance to other antibiotic classes, particularly macrolides. [37]
Resistance to third-generation fluoroquinolones is also causing concern among
clinicians.[38, 39] Although the current reported frequency is low, indiscriminate use
of these agents might eventually limit the efficacy of this class of agents against
pneumococcal infections. The S. pneumoniae strains are also beginning to
demonstrate tolerance to vancomycin, with multiple isolates identified. [40, 41]
Fortunately, these isolates remain susceptible to most other antibiotics, including
fluoroquinolones and linezolid.
Pharmacologic Agents
Three available antibioticsdalfopristin, linezolid, and daptomycin—have activity
against multidrug-resistant gram-positive organisms. These agents were primarily
developed to target staphylococci and enterococci, but they also have significant
activity against streptococci. Whereas quinupristin-dalfopristin and linezolid have
been on the market for a few years, daptomycin was only approved in September
2003. These agents have relatively limited indications and are often employed for
off-label uses. Table 1 compares their pharmacokinetic, pharmacodynamic, and
other characteristics.
Quinupristin-Dalfopristin
Quinupristin-dalfopristin, a streptogramin antibiotic, was introduced in the fall of
1999 for treatment of serious or life-threatening bacteremia caused by vancomycinresistant E. faecium (VREF) and skin and skin structure infections due to
methicillin-sensitive S. aureus (MSSA) and S. pyogenes.[42] It lacks activity against
E. faecalis. Regardless of the approved indications, this agent has primarily been
used to treat quinupristin-dalfopristin-susceptible infections caused by VREF. The
combination drug works by binding to different sites on the 50S subunit of bacterial
ribosomes and disrupting early and late stages of bacterial protein synthesis.
Binding of group A streptogramin (dalfopristin) to the ribosome causes a
conformational change that increases the binding affinity for group B streptogramin
(quinupristin). Quinupristin-dalfopristin is bacteriostatic against E. faecium but has
bactericidal activity against staphylococcal strains.
Adverse events have been significant for this combination drug ( Table 1 ).[10, 42, 43]
Most notable are venous events at the infusion site such as inflammation, pain, and
edema. Resistance is also a concern, and multiple mechanisms of resistance have
been identified. For the individual components, these may include inactivating
enzymes (vat), efflux (lsa), and target modification (erm).[44] Although resistance
to quinupristin-dalfopristin has been observed in staphylococci isolates, most
instances of resistance have been seen in enterococci, with susceptibility rates
decreasing in 2000 to approximately 83% for E. faecium from greater than 90% in
earlier years.[45]
Linezolid
Linezolid, a semisynthetic antibiotic, is the first available agent in the oxazolidinone
class. It was brought to market in the spring of 2000 with the following indications:
treatment of complicated and uncomplicated skin and skin structure infections,
infections caused by S. pyogenes and S. agalactiae, nosocomial pneumonia (MSSA,
MRSA, penicillin-susceptible S. pneumoniae), community-acquired pneumonia
(MSSA and penicillin-susceptible S. pneumoniae), and VREF infections.[43] An
additional indication was approved in 2003 for treatment of diabetic foot infections
caused by S. aureus (MSSA and MRSA). However, as with quinupristin-dalfopristin,
most use of this drug is for treatment of VRE (E. faecium or E. faecalis) infections
at any site.
Some recent data suggest that linezolid may be superior to vancomycin in
ventilator-acquired pneumonia due to MRSA.[46, 47] However, other studies have
found comparable results for linezolid and vancomycin for clinical cure rates and
microbiologic success rates.[48, 49] Retrospective studies combining data from two
prospective studies have not yielded clear conclusions, since several factors were
not taken into account, such as vancomycin levels in failure patients and
differences in baseline patient characteristics between the two groups.
Linezolid acts by binding to the 23S bacterial ribosomal RNA of the 50S subunit,
thus preventing formation of the 70S initiation complex. It displays bacteriostatic
activity against all gram-positive isolates except for penicillin-susceptible S.
pneumoniae, in which it is bactericidal. Resistance to linezolid, documented during
clinical studies as well as after Food and Drug Administration (FDA) approval, has
occurred primarily in enterococci; however, a small number of strains of
staphylococci and streptococci isolated in animal models also show resistance. [50-52]
Moreover, resistance has been observed in patients without past exposure to this
drug class.[53] The mecha-nism of resistance is a mutation in the 23S rRNA.
A significant number of adverse events have also been observed, particularly during
postmarketing surveillance. Myelosuppression (anemia, leukopenia, pancytopenia,
and thrombocytopenia) has been observed in patients receiving the drug for 2 or
more weeks, with most patients affected after 28 days. This adverse event is dose
and duration dependent. However, myelosuppression has also occurred in patients
treated with shorter courses (< 28 days) of therapy. Weekly monitoring for
myelosuppression is recommended in patients receiving an extended course of
linezolid or who have preexisting myelosuppression. Studies comparing the
occurrence of thrombocytopenia between linezolid and vancomycin in critically ill
patients showed no statistically significant difference, except in patients who
received vancomycin before switching to oral linezolid.[54, 55] Despite these findings,
studies in other patient populations need to be conducted to fully assess the
hematologic effects of linezolid. Other events that have occurred with linezolid
include neuropathy (peripheral and optic) and lactic acidosis.[43]
It is important to note that of quinupristin-dalfopristin, linezolid, and daptomycin,
linezolid is the only one that is available in an oral dosage form, making it a
desirable choice for long-term outpatient therapy. Although the implications of
using a bacteriostatic agent for outpatient treatment of chronic infections such as
osteomyelitis are not fully known at this time, the potential for resistance
development in this scenario is a concern.[56]
Daptomycin
Daptomycin is the first in the class of lipopeptide antibiotics, which are derived from
fermentation of Streptomyces roseosporus. It was originally developed and
investigated by Eli Lilly and Company at a dosage of 3 mg/kg every 12 hours in the
early 1990s. During clinical trials numerous patients developed elevated levels of
creatine kinase. In addition, one patient who received suboptimal dosing (1.6
mg/kg every 12 hrs) in a clinical endocarditis study experienced treatment failure
resulting in the development of a resistant isolate. Because of these issues and the
absence of significant gram-positive resistant pathogens at the time, the drug's
development was discontinued.
With renewed interest in an alternative agent for resistant gram-positive
organisms, Cubist Pharmaceuticals, Inc., licensed all rights to daptomycin in 1997
and began moving ahead with in vitro and in vivo studies with a modified dosing
regimen. The agent was approved by the FDA in September 2003 with an indication
for treatment of complicated skin and skin structure infections, including diabetic
foot and decubitus ulcers.[10] Approved organisms include S. aureus (including
MRSA), S. pyogenes, S. agalactiae, S. dysgalactiae, E. faecalis (vancomycin
susceptible), and viridans group streptococci. In addition, both in vitro and in vivo
data show activity against VRE (E. faecium and E. faecalis) as well as penicillinresistant streptococci. However, susceptibility breakpoints for E. faecium have not
yet been established. Currently, this agent is being used primarily off-label for any
serious gram-positive infection for which the clinician believes it necessary,
including endocarditis and osteomyelitis (although most clinicians are
recommending higher dosages than 4 mg/kg, such as 6-8 mg/kg, every 24 hrs).
It is important to note that daptomycin is not being recommended for treatment of
pneumonia. This decision follows a community-acquired pneumonia study in which
daptomycin did not demonstrate equivalent efficacy to ceftriaxone.[57] Therefore,
caution is warranted until further data and experience with this drug are known.
Daptomycin differs from other antibiotics in that its mechanism of action involves
calcium-dependent binding to the bacterial membrane. Binding results in channel
formation within the cell wall, allowing for the efflux of potassium, with
accompanying cell depolarization and cell death. Bacteria killed by daptomycin
remain intact, unlike bacteria killed by other agents that also act on cell walls. It is
thought that this characteristic of daptomycin may prove beneficial in treating
pathogens that produce toxin. Toxin production is associated with severe infections
such as toxic shock syndrome (group A streptococci and staphylococci) and scalded
skin syndrome. Daptomycin displays bactericidal activity against all gram-positive
organisms, including multidrug-resistant isolates.
Daptomycin's adverse effects are similar to those associated with other antibiotics,
including headache, diarrhea, and rash. Elevations in creatine kinase levels have
occurred with the drug. However, most documented cases occurred in early clinical
trials, when it was dosed every 12 hours.[58] Later, a study in dogs demonstrated
that by extending the dosing interval this reversible effect could be minimized; the
same study also showed that creatine kinase level elevations were similar to
exercise-induced effects.[59] Muscle effects with the once-daily dosage regimen are
minimal; they are reported in clinical studies involving complicated skin and skin
structure infections at a rate of 2.8%, compared with 1.8% for conventional
therapy (semisynthetic penicillin or vancomycin).[10]
Investigational Agents
Oritavancin is an investigational glycopeptide that retains activity against
vancomycin-resistant isolates due to slight differences from vancomycin in its
mechanism of action. Its activity encompasses VRE, regardless of the presence of
vanA, vanB, or vanC genes; VISA; and VRSA strains.[60-62] Another difference
between oritavancin and vancomycin is that oritavancin exhibits concentrationdependent bactericidal activity in in vitro studies. This agent has a terminal half-life
of 132-356 hours. It has been evaluated in phase III clinical trials of complicated
skin and skin structure infections. These studies found no statistical difference
between oritavancin and vancomycin. However, additional safety data have been
requested by the FDA before a new drug application can be submitted.
Dalbavancin is a glycopeptide antibiotic that, like oritavancin, has bactericidal
activity against multidrug-resistant gram-positive organisms. It has a long half-life
of approximately 10 days, allowing for a once-weekly dosing regimen.[63] Phase II
and III clinical trials have compared dalbavancin with the standard of care in skin
and soft-tissue infections and catheter-related bloodstream infections.[64-68] (For
uncomplicated skin and soft-tissue infections the standard of care is intravenous
cefazolin followed by oral cephalexin; for complicated skin and soft-tissue infections
the standard of care is linezolid; for MRSA and catheter-related bloodstream
infections the standard of care is vancomycin). Both phase II trials demonstrated
clinical success rates of 94.1% for skin and soft-tissue infections and 87% for
catheter-related bloodstream infections in patients who received two or more doses
of dalbavancin. The success rates for the two comparator groups were 76.2% and
50%, respectively.[63-66, 68] Vicuron Pharmaceuticals submitted a new drug
application at the end of 2004. The FDA granted priority review status for treatment
of complicated skin and soft tissue infections.
Tigecycline, from the glycylcycline class of antibiotics, is a derivative of minocycline,
a tetracycline. In vitro studies have demonstrated activity against gram-positive,
gram-negative, and anaerobic organisms. It retains activity against gram-positive
pathogens that are resistant to penicillins or vancomycin. Two phase II open-label
clinical trials have evaluated this agent in complicated skin and skin structure
infections and complicated intraabdominal infections.[69, 70] Clinical cure rates for
these studies were 67-74%. Phase III clinical trials have been completed for both
complicated intraabdominal and complicated skin and skin structure infections, both
achieving their primary end point. The company received priority review status in
early 2005 from the FDA.
Discussion
Antibiotic Penetration
Site of infection may play a role in agent selection. Unfortunately, antibiotic
penetration data for the newer agents are not well defined. Quinupristin-dalfopristin
demonstrates good penetration into tissues such as the kidney, liver, and spleen. [71]
However, animal studies have shown quinupristin-dalfopristin to have poor
penetration into the central nervous system.[71, 72] Studies of lung penetration have
had variable outcomes. Animal models and clinical studies have demonstrated
efficacy in the treatment of pneumonia.[72, 73] Minimal data are available on bone
and joint penetration; however, animal studies and clinical data seem to indicate
efficacy.[74]
Linezolid has also been shown to have good penetration throughout the body,
including lungs, bone, and cerebrospinal fluid.[75-77] It was efficacious in treating
CNS shunt infections.[77]
Daptomycin has good penetration into tissues, particularly vascularized areas such
as the kidneys.[78] However, a study of its pharmacokinetics and penetration into
inflammatory fluid showed only 68.4% penetration.[79] Because daptomycin rapidly
penetrated into the fluid, its low extent of penetration may reflect high protein
binding and the relatively low amount of protein in the inflammatory exudates. In a
study of community-acquired pneumonia, daptomycin did not achieve the primary
end point of demonstrating non-inferiority in comparison with ceftriaxone.[57] A
phase III clinical trial of daptomycin 6 mg/kg/24 hours in patients with S. aureus
bacteremia and endocarditis is ongoing.[80, 81] At this time no clinical data are
available regarding the efficacy or penetration of daptomycin in central nervous
system and bone infections.
Combination Therapy
Some studies have evaluated the use of combination therapy with these new
agents for treatment of resistant gram-positive infections. The data are incomplete
and inconclusive, with many studies reporting conflicting information. However,
some studies have demonstrated benefits of combination therapy, including
quinupristin-dalfopristin in combination with doxycycline or ampicillin against VREF
and with rifampin against MRSA.[82] Initial in vitro analysis demonstrates that
daptomycin may exhibit synergy in combination with ampicillin and rifampin against
VRE and with aminoglycosides and oxacillin against MRSA.[83-85]
Current Therapeutic Recommendations
Limited data on a small set of indications with these agents create a dilemma for
clinicians when seeking the best treatment option. For treatment of VRE infections,
linezolid and daptomycin have typically been the preferred agents, since both have
in vitro or in vivo activity against both enterococcal strains. For MRSA unresponsive
to vancomycin therapy, the choice of a treatment alternative depends on the
location of the infection. For pneumonia, linezolid has efficacy against MRSA. In
contrast, daptomycin is not recommended for treatment of pneumonia, based on
the results of a published trial. Treatment for bacteremia often depends on a
patient's characteristics. In particular, if a patient is immuno-compromised,
clinicians prefer to use a bactericidal agent. Deep-seated infections with VRE or
MRSA, such as endocarditis or osteomyelitis, may also warrant selection of a
bactericidal agent (quinupristin-dalfopristin or daptomycin) if the pathogen is
susceptible. Linezolid is an option for long-term outpatient therapy, since it is
available in an oral formulation. However, prudent use is necessary to limit the
potential for resistance development. In all situations, the risk of adverse events
relative to a specific patient-care scenario must be taken into account. When VISA
or VRSA is suspected, an isolate should be evaluated according to NCCLS
guidelines.[86-88] Treatment for these organisms should be adjusted according to
susceptibilities. New agents (quinupristin-dalfopristin, linezolid, daptomycin), as
well as some traditional agents, may be therapeutic options. However, combination
therapy may be warranted.
Conclusion
Due to the continuing trend of increased resistance among gram-positive
organisms, it is imperative to continue the development of new antibiotics.
However, quinupristin-dalfopristin, linezolid, and daptomycin provide valuable
alternatives to vancomycin. A better understanding of where these agents belong in
therapy should become more evident over the next few years. In the meantime, it
is important to limit their use to treatment of documented resistant infections or
infections that recur despite adequate treatment with vancomycin.
Table 1. Comparison of Agents[10, 42, 43]
QuinupristinDalfopristin
Linezolid
Daptomycin
Dosage
7.5 mg/kg q8h or
7.5 mg/kg q12h
600 mg q12h or
400 mg q12h
4 mg/kg q12h
Route of
administration
i.v.
i.v. or p.o.
i.v.
Agent
Dosage adjustments None required for
renal impairment
No data available
for hepatic
insufficiency
Volume of
distribution (L/kg)
None required for renal Clcr ≤ 30 ml/min:
or hepatic insufficiency increase dosing
interval to q48h
None required for
hepatic impairment
Quinupristin: 0.45 0.55
Dalfopristin: 0.24
Protein binding (%) Quinupristin = 5578
31
Dalfopristin = 1126
0.1
91-95
Elimination halflife (hrs)
Quinupristin =
0.9-1.1
5-8
Dalfopristin = 0.47
Pharmacodynamic
predictor
Concentration
dependent
Concentration
independent
Cidality
Cidal except
against
enterococci
Static except against
Cidal against all
penicillin-susceptible S. strains
pneumoniae
Adverse effects
Venous events,
myalgias
Myelosuppression
Creatine kinase
elevations
Significant
interactions
Inhibits
cytochrome P450
3A4 metabolism
None
None
Cost/day
(average wholesale
price
based on 70-kg
patient
for weight-based
doses)
$302-453
p.o. $129, i.v. $170
$168
Clcr = creatinine clearance.
8-9
Concentration
dependent
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