DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1536 streptogramin A, in a 30:70 ratio. These compounds are
semisynthetic derivatives of naturally occurring pristinamycins,
produced by Streptomyces pristinaespiralis.
Pristinamycin has been available in France for >30
years for oral treatment of staphylococcal infections.
Quinupristin and dalfopristin are more soluble derivatives
of pristinamycin IA and pristinamycin IIA, respectively,
and therefore are suitable for intravenous
administration.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
O
S
H H
H
CH 2
O
H 2 C
H
N
H
N(CH 3 ) 2
O
CH 3
QUINUPRISTIN
O
H
OH
N
H H
CH 3
H 3 C
O
O
O
H H
3 C
N
CH
H
O
N
CH O 3 O
S
O H
CH 2
CH 2 N(C 2 H 5 ) 2
DALFOPRISTIN
H CH 2 CH 3
NH
H CH 3
Antimicrobial Activity. Quinupristin/dalfopristin is active against
gram-positive cocci, including S. pneumoniae, beta- and alphahemolytic
strains of streptococci, E. faecium (but not E. faecalis),
and coagulase-positive and coagulase-negative strains of staphylococci
(Table 55–2). Strains are considered sensitive if they are inhibited
by concentrations of ≤1 μg/mL. The combination is largely
inactive against gram-negative organisms, although Moraxella
catarrhalis and Neisseria spp. are susceptible. It also is active against
organisms responsible for atypical pneumonia, M. pneumoniae,
Legionella spp., and Chlamydia pneumoniae. The combination is
bactericidal against streptococci and many strains of staphylococci
but bacteriostatic against E. faecium.
Mechanism of Action. Quinupristin and dalfopristin are protein synthesis
inhibitors that bind the 50S ribosomal subunit. Quinupristin
binds at the same site as macrolides and has a similar effect, with
inhibition of polypeptide elongation and early termination of protein
synthesis. Dalfopristin binds at a site nearby, resulting in a conformational
change in the 50S ribosome, synergistically enhancing
the binding of quinupristin at its target site. Dalfopristin directly
interferes with polypeptide-chain formation. In many bacterial
N
O
O
H
N
H
H
O
O
N
O
O
H NH OH
C
O
N
species, the net result of the cooperative and synergistic binding of
these two molecules to the ribosome is bactericidal activity.
Resistance to Streptogramins. Resistance to quinupristin is mediated
by MLS type B resistance determinants (e.g., ermA and ermC
in staphylococci and ermB in enterococci), encoding a ribosomal
methylase that prevents binding of drug to its target; or vgb or vgbB,
which encode lactonases that inactivate type B streptogramins
(Allignet et al., 1998; Bozdogan and Leclercq, 1999). Resistance to
dalfopristin is mediated by vat, vatB, vatC, vatD, and satA, which
encode acetyltransferases that inactivate type A streptogramins
(Soltani et al., 2000); or staphylococcal genes vga and vgaB, which
encode ATP-binding efflux proteins that pump type A streptogramins
out of the cell (Bozdogan and Leclercq, 1999). These resistance
determinants are located on plasmids that may be transferable by
conjugative mobilization. Resistance to quinupristin/dalfopristin
always is associated with a resistance gene for type A streptogramins.
Genes encoding resistance to type B streptogramins also
may be present but are not sufficient by themselves to produce resistance.
Methylase-encoding erm genes, however, can render the combination
bacteriostatic instead of bactericidal, making it ineffective
in certain infections in which bactericidal activity is necessary for
cure, such as endocarditis.
Absorption, Distribution, and Excretion. The combination of
quinupristin/dalfopristin is administered only by intravenous infusion
over at least 1 hour. It is incompatible with saline and heparin and
should be dissolved in 5% dextrose in water. Steady-state peak serum
concentrations in healthy male volunteers are ~3 μg/mL of quinupristin
and 7 μg/mL of dalfopristin with a 7.5-mg/kg dose administered
every 8 hours. The t 1/2
is 0.85 hour for quinupristin and 0.7 hour
for dalfopristin. The volume of distribution is 0.87 L/kg for quinupristin
and 0.71 L/kg for dalfopristin. Hepatic metabolism by conjugation
is the principal means of clearance for both compounds, with
80% of an administered dose eliminated by biliary excretion. Renal
elimination of active compound accounts for most of the remainder.
No dosage adjustment is necessary for renal insufficiency.
Pharmacokinetics are not significantly altered by peritoneal dialysis or
hemodialysis. The area under the plasma concentration curve of active
component and its metabolites is increased by 180% for quinupristin
and 50% for dalfopristin by hepatic insufficiency. No adjustment is
recommended unless the patient is unable to tolerate the drug, in which
case the dosing frequency should be reduced from 8 to 12 hours.
Therapeutic Uses and Dosage. Quinupristin/dalfopristin is approved in
the U.S. for treatment of infections caused by vancomycin-resistant
strains of E. faecium and complicated skin and skin-structure infections
caused by methicillin-susceptible strains of S. aureus or S. pyogenes
(Nichols et al., 1999). In Europe it also is approved for treatment of
nosocomial pneumonia and infections caused by methicillin-resistant
strains of S. aureus (Fagon et al., 2000). In open-label, nonrandomized
studies, clinical and microbiological cure rates for a variety of infections
caused by vancomycin-resistant E. faecium were ~70% with quinupristin/dalfopristin
at a dose of 7.5 mg/kg every 8-12 hours (Moellering
et al., 1999). Quinupristin/dalfopristin should be reserved for treatment
of serious infections caused by multiple-drug-resistant gram-positive
organisms such as vancomycin-resistant E. faecium.
Untoward Effects. The most common side effects are infusion-related
events, such as pain and phlebitis at the infusion site and arthralgias
and myalgias. Phlebitis and pain can be minimized by infusion of
drug through a central venous catheter. Arthralgias and myalgias,