Quinupristin-dalfopristin combined with beta-lactams for treatment of experimental endocarditis due to Staphylococcus aureus constitutively resistantto macrolide-lincosamide-streptogramin B antibiotics
J. Vouillamoz et al., Quinupristin-dalfopristin combined with beta-lactams for treatment of experimental endocarditis due to Staphylococcus aureus constitutively resistantto macrolide-lincosamide-streptogramin B antibiotics, ANTIM AG CH, 44(7), 2000, pp. 1789-1795
Quinupristin-dalfopristin (Q-D) is an injectable streptogramin active again
st most gram-positive pathogens, including methicillin-resistant Staphyloco
ccus aureus (MRSA). In experimental endocarditis, however, Q-D was less eff
icacious against MRSA isolates constitutively resistant to macrolide-lincos
amide-streptogram B (C-MLSB) than against MLSB-susceptible isolates. To cir
cumvent this problem, we used the checkerboard method to screen drug combin
ations that would increase the efficacy of Q-D against such bacteria, beta-
Lactams consistently exhibited additive or synergistic activity with Q-D, G
lycopeptides, quinolones, and aminoglycosides were indifferent. No drugs we
re antagonistic. The positive Q-D-beta-lactam interaction was independent o
f MLSB or beta-lactam resistance, Moreover, addition of Q-D at one-fourth t
he MIC to flucloxacillin-containing plates decreased the flucloxacillin MIC
for MRSA from 500 to 1,000 mg/liter to 30 to 60 mg/liter, Yet, Q-D-beta-la
ctam combinations mere not synergistic in bactericidal tests. Rats with aor
tic vegetations were infected with two C-MLSB-resistant MRSA isolates (isol
ates AW7 and P8) and were treated for 3 or 5 days with drug dosages simulat
ing the following treatments in humans: (i) Q-D at 7 mg/kg two times a day
(b.i.d.) (a relatively low dosage purposely used to help detect positive dr
ug interactions), (ii) cefamandole at constant levels in serum of 30 mgl/it
er, (iii) cefepime at 2 g b.i.d., (iv) Q-D combined with either cefamandole
or cefepime. Any of the drugs used alone resulted in treatment failure, In
contrast, Q-D plus either cefamandole or cefepime significantly decreased
valve infection compared to the levels of infection for both untreated cont
rols and those that received monotherapy (P < 0.05). Importantly, Q-D preve
nted the growth of highly beta-lactam-resistant MRSA in vivo, The mechanism
of this beneficial drug interaction is unknown, However, Q-D-beta-lactam c
ombinations might be useful for the treatment of complicated infections cau
sed by multiple organisms, including MRSA.