quinupristin-dalfopristin and Pneumococcal-Infections

Pneumococcal macrolide resistance is usually expressed as one of two phenotypes: the M phenotype conferred by the mef gene or the MLSB phenotype caused by modification of ribosomal targets, most commonly mediated by an erm methylase. Target-site modification leading to antibiotic resistance can also occur due to sequence mutations within the 23S rRNA or the L4 and L22 riboproteins. We screened 4,535 invasive isolates resistant to erythromycin and 18 invasive isolates nonsusceptible to quinupristin-dalfopristin (Q-D) to deduce the potential mechanisms involved. Of 4,535 erythromycin-resistant isolates, 66.2% were polymerase chain reaction (PCR)-positive for mef alone, 17.8% for ermB alone, and 15.1% for both mef and ermB. Thirty-seven isolates (0.9%) were PCR negative for both determinants. Of these, 3 were positive for ermA (subclass ermTR) and 25 had chromosomal mutations. No chromosomal mutations (in 23S rRNA, rplD, or rplV) nor any of the macrolides/lincosamides/streptogramin (MLS) resistance genes screened for (ermT, ermA, cfr, lsaC, and vgaA) were found in the remaining nine isolates. Of 18 Q-D nonsusceptible isolates, 14 had chromosomal mutations and one carried both mef and ermB; no chromosomal mutations or other resistance genes were found in 3 isolates. Overall, we found 28 mutations, 13 of which have not been previously described in Streptococcus pneumoniae. The role of these mutations remains to be confirmed by transformation assays.

Topics: Anti-Bacterial Agents; Chromosomes, Bacterial; Drug Resistance, Multiple, Bacterial; Erythromycin; Genes, Bacterial; Humans; Interspersed Repetitive Sequences; Lincosamides; Macrolides; Microbial Sensitivity Tests; Phenotype; Pneumococcal Infections; Streptococcus pneumoniae; Streptogramins; United States; Virginiamycin

Sickle cell disease (SCD) is a risk factor for fatal pneumococcal infection. Nonsusceptibilty to quinupristin-dalfopristin (Q-D) was absent from 105 non-SCD-associated pneumococcal isolates but was present in 33/148 (22%) SCD-associated isolates. One-third of the isolates harbored a known resistance mechanism. Q-D is not optimal for use for the treatment of pneumococcal infection in SCD patients.

Topics: Anemia, Sickle Cell; Anti-Bacterial Agents; Clindamycin; Drug Resistance, Bacterial; Erythromycin; Humans; Microbial Sensitivity Tests; Phylogeny; Pneumococcal Infections; Serotyping; Streptococcus pneumoniae; Virginiamycin

To date, 86 of 7,746 macrolide-resistant Streptococcus pneumoniae isolates from 1999 to 2002 PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) surveillance studies were negative for methylase and efflux mechanisms. Mutations in 23S rRNA or the genes encoding riboprotein L4 or L22 were found in 77 of 86 isolates. Six isolates were resistant to quinupristin-dalfopristin and two were resistant to linezolid, while telithromycin demonstrated good activities against all isolates.

Topics: Acetamides; Anti-Bacterial Agents; Dose-Response Relationship, Drug; Drug Resistance, Bacterial; Humans; Ketolides; Linezolid; Macrolides; Mutation; Oxazolidinones; Pneumococcal Infections; Ribosomes; RNA, Ribosomal, 23S; Streptococcus pneumoniae; Virginiamycin

Topics: Acetamides; Anti-Infective Agents; Drug Resistance, Bacterial; Drug Therapy, Combination; Erythromycin; Humans; In Vitro Techniques; Linezolid; Oxazolidinones; Penicillin Resistance; Pneumococcal Infections; Streptococcus pneumoniae; Virginiamycin

The efficacy of different antibiotics was compared in an experimental model of aortic valve endocarditis in rabbits, using a serotype 19 strain of Streptococcus pneumoniae resistant to penicillin (MIC 12 mg/L) and ceftriaxone (MIC 12 mg/L). The results were compared with those of a control group, which received no treatment. One hundred and nineteen animals were treated with one of the following antibiotic regimens: im procaine penicillin G at a dosage of 300,000 U/kg weight/12 h (16 animals); iv trovafloxacin, 13.3 mg/kg/12 h (31 animals); iv ceftriaxone, 75 mg/kg/24 h (21 animals); iv vancomycin, 20 mg/kg/12 h (15 animals) and im quinupristin-dalfopristin, 30 mg/kg/8 h (20 animals). All the antibiotics used in this study proved to be efficient in reducing numbers of S. pneumoniae and in increasing the percentage of aortic vegetations that were rendered sterile compared with the control group. Penicillin at the dosage used in our study was capable of achieving serum concentrations two or three times greater than the MIC, thus demonstrating its effectiveness as an antibiotic for this endocarditis model. No significant difference was observed between the effects of vancomycin, quinupristin-dalfopristin and penicillin. Vancomycin proved to be more efficient than trovofloxacin in reducing the bacterial load and increasing the numbers sterilized. There was also a tendency for this antibiotic to be more effective than ceftriaxone in reducing the bacterial load of the vegetations. There was a statistically significant correlation between the weight of the vegetations and their bacterial load. In the light of these results, vancomycin and quinupristin-dalfopristin may be considered suitable alternatives to penicillin for the treatment of penicillin-resistant S. pneumoniae endocarditis.

Topics: Animals; Anti-Infective Agents; Ceftriaxone; Disease Models, Animal; Drug Resistance, Multiple; Endocarditis, Bacterial; Fluoroquinolones; Humans; Male; Naphthyridines; Penicillin Resistance; Penicillins; Pneumococcal Infections; Rabbits; Streptococcus pneumoniae; Vancomycin; Virginiamycin

Eighty-five recent isolates of Streptococcus pneumoniae from patients with invasive disease were examined for their susceptibility to erythromycin, clindamycin, penicillin and quinupristin-dalfopristin by E test. A novel duplex PCR assay was used to detect the presence of the erm(B) or mef(A) genes in all of the erythromycin-resistant isolates. All of the strains tested were susceptible to the combination quinupristin-dalfopristin, regardless of their susceptibility to penicillin or to erythromycin. By duplex PCR, two-thirds of the erythromycin-resistant strains harbored erm, and one-third harbored mef. The activity of quinupristin-dalfopristin was not influenced by the genetic determinant of erythromycin resistance. The in vitro susceptibility of S. pneumoniae to quinupristin-dalfopristin is promising for future use; however, it is important to monitor the possible emergence of resistance.

Topics: Anti-Bacterial Agents; Clindamycin; Drug Resistance, Bacterial; Drug Therapy, Combination; Electrophoresis, Agar Gel; Erythromycin; Humans; Italy; Microbial Sensitivity Tests; Penicillin Resistance; Penicillins; Pneumococcal Infections; Polymerase Chain Reaction; Streptococcus pneumoniae; Virginiamycin

Four different compounds belonging to the macrolide-lincosamide-streptogramin B (MLSb) class of antimicrobial agents were tested against 611 Streptococcus pneumoniae strains. The ketolide (HMR 3647, previously RU66647) and the streptogramin (quinupristin-dalfopristin) were both active against pneumococci with high-level MLSb resistance (clindamycin-resistant strains) as well as those with low-level macrolide resistance (clindamycin-susceptible strains).

Topics: Anti-Bacterial Agents; Clindamycin; Erythromycin; Humans; Ketolides; Macrolides; Penicillin Resistance; Phenotype; Pneumococcal Infections; Streptococcus pneumoniae; Virginiamycin

RP 59500 is a new semisynthetic injectable streptogramin antibiotic composed of two compounds which interact synergically, RP 57669 and RP 54476, derived from pristinamycin IA and pristinamycin IIB, respectively. The bacteristatic and bactericidal activities of RP 57669 and RP 54476 alone or combined in various proportions were tested by the chequerboard dilution technique. The fractional inhibitory concentration (FIC) index was determined for 14 Staphylococcus aureus isolates (including methicillin- and macrolide-resistant strains) and one culture collection strain. The FIC index was found to be much lower than 0.5, indicating the presence of synergy for all strains tested, whatever their resistance pattern. The ED50 of RP 57669 and RP 54476 in various combinations were also determined in three experimental murine models of septicaemia, caused by either S. aureus or Streptococcus pneumoniae, and a thigh abscess model caused by S. aureus. The combinations which performed best in the model of septicaemia were those in which the RP 57669: RP 54476 ratio ranged from 16:84 to 92:8, while those active against the thigh abscess model had ratios ranging from 8:92 to 84:16. That the drugs were active over a wide range of ratios suggests that synergy will be maintained even if one drug is cleared more rapidly than the other. The combination of 30:70, referred to as RP 59500, was selected for further studies, both in vitro and in various experimental models of infections.

Topics: Abscess; Animals; Drug Resistance, Microbial; Drug Synergism; Humans; In Vitro Techniques; Mice; Microbial Sensitivity Tests; Pneumococcal Infections; Staphylococcal Infections; Staphylococcus aureus; Streptococcus pneumoniae; Thigh; Virginiamycin