The mechanism of resistance to the streptogramin antibiotics quinupristin and dalfopristin was studied in a Staphylococcus aureus clinical isolate selected under quinupristin-dalfopristin therapy, in four derivatives of S. aureus RN4220 selected in vitro, and in a mutant selected in a model of rabbit aortic endocarditis. For all strains the MICs of erythromycin, quinupristin, and quinupristin-dalfopristin were higher than those for the parental strains but the MICs of dalfopristin and lincomycin were similar. Portions of genes for domains II and V of 23S rRNA and the genes for ribosomal proteins L4 and L22 were amplified and sequenced. All mutants contained insertions or deletions in a protruding ␤ hairpin that is part of the conserved C terminus of the L22 protein and that interacts with 23S rRNA. Susceptible S. aureus RN4220 was transformed with plasmid DNA encoding the L22 alteration, resulting in transformants that were erythromycin and quinupristin resistant. Synergistic ribosomal binding of streptogramins A and B, studied by analyzing the fluorescence kinetics of pristinamycin I A -ribosome complexes, was abolished in the mutant strain, providing an explanation for quinupristin-dalfopristin resistance.Streptogramin antibiotics are a mixture of two classes of chemically distinct components, designated streptogramins A and B. Quinupristin-dalfopristin is a semisynthetic injectable streptogramin, a mixture of quinupristin and dalfopristin, which are semisynthetic derivatives of pristinamycin I A (PI A ; streptogramin B) and pristinamycin II A (PII A ; streptogramin A), respectively. The binding of these factors to the 50S ribosomal subunit causes inhibition of protein synthesis. Alone, each factor has a moderate bacteriostatic activity, but the combination can display a bactericidal synergistic effect, which has been attributed to the synergistic binding of the factors to their ribosomal target site (11).Quinupristin-dalfopristin is active against a wide range of gram-positive organisms including methicillin-resistant staphylococci and vancomycin-resistant Enterococcus faecium (33). Since streptogramins A and B are chemically unrelated and have different binding sites, the mechanisms of resistance to these two streptogramins are different. Resistance to each component of the streptogramins in both staphylococci and enterococci has been reported (13, 32). The most common type of resistance to streptogramin B antibiotics is related to the production of ribosomal methylases encoded by erm genes. Resistance results from decreased component B binding to the ribosome. Cross-resistance between streptogramins B and all macrolides and lincosamides occurs because these antimicrobials have overlapping binding sites, yielding the so-called macrolide-lincosamide-streptogramin B (MLS B ) phenotype. The synergistic inhibitory activity of the two streptogramin components is conserved even when the 23S rRNA is modified by an Erm methylase although the bactericidal activity of the streptogramin combination is altered. By contr...

During antibiotic treatments, active residuals reaching the colon profoundly affect the bacterial flora resulting in the emergence of resistance. To prevent these effects, we developed an enteric-coated formulated activated-charcoal based product, DAV132, meant to deliver its adsorbent to the ileum and neutralize antibiotic residues in the proximal colon. In a randomized, control, crossover study, the plasma pharmacokinetics of the probe drugs amoxicillin (500 mg) absorbed in the proximal intestine, and sulfapyridine (25 mg) metabolized from sulfasalazine in the cecum and rapidly absorbed, were compared after a single administration in 18 healthy subjects who had received DAV132, uncoated formulated activated charcoal (FAC) or water 16 and 8 hours before, concomitantly with the probe drugs, and 8 hours thereafter. The AUC0-96 h of amoxicillin was reduced by more than 70% when it was taken with FAC, but bioequivalent when it was taken with water or DAV132. By contrast, the AUC0-96 h of sulfapyridine was reduced by more than 90% when administered with either FAC or DAV132 in comparison with water. The results show that DAV132 can selectively adsorb drug compounds in the proximal colon, without interfering with drug absorption in the proximal small intestine, thereby constituting a proof of concept that DAV132 actually functions in humans.

Quinupristin-dalfopristin (Q-D

No abstract

IntroductionAlthough Pseudomonas aeruginosa is a leading pathogen responsible for ventilator-associated pneumonia (VAP), the excess in mortality associated with multi-resistance in patients with P. aeruginosa VAP (PA-VAP), taking into account confounders such as treatment adequacy and prior length of stay in the ICU, has not yet been adequately estimated.MethodsA total of 223 episodes of PA-VAP recorded into the Outcomerea database were evaluated. Patients with ureido/carboxy-resistant P. aeruginosa (PRPA) were compared with those with ureido/carboxy-sensitive P. aeruginosa (PSPA) after matching on duration of ICU stay at VAP onset and adjustment for confounders.ResultsFactors associated with onset of PRPA-VAP were as follows: admission to the ICU with septic shock, broad-spectrum antimicrobials at admission, prior use of ureido/carboxypenicillin, and colonization with PRPA before infection. Adequate antimicrobial therapy was more often delayed in the PRPA group. The crude ICU mortality rate and the hospital mortality rate were not different between the PRPA and the PSPA groups. In multivariate analysis, after controlling for time in the ICU before VAP diagnosis, neither ICU death (odds ratio (OR) = 0.73; 95% confidence interval (CI): 0.32 to 1.69; P = 0.46) nor hospital death (OR = 0.87; 95% CI: 0.38 to 1.99; P = 0.74) were increased in the presence of PRPA infection. This result remained unchanged in the subgroup of 87 patients who received adequate antimicrobial treatment on the day of VAP diagnosis.ConclusionsAfter adjustment, and despite the more frequent delay in the initiation of an adequate antimicrobial therapy in these patients, resistance to ureido/carboxypenicillin was not associated with ICU or hospital death in patients with PA-VAP.