Cross-resistance analyses and molecular typing of Staphylococcus aureus and Streptococcus spp. isolates resistant to quinupristin/dalfopristin

J Antimicrob Chemother 1999; 44: 847-849 Sir, During the past two decades Gram-positive bacteria, predominantly staphylococci and streptococci, have re-emerged as important pathogens. Staphylococci, in particular, have demonstrated a remarkable propensity for acquiring mechanisms of resistance to every new antimicrobial to become available and for spreading among patients, institutions and communities. More recently, there have also been increasing concerns about β-lactam resistance in Streptococcus pneumoniae and other streptococci. Clearly, there is a pressing need to identify novel compounds that can be used as therapy for patients with infections caused by these organisms.1 Quinupristin/dalfopristin, a combination of two streptogramins, is one such agent. It has been shown to have excellent activity in vitro against a broad range of staphylococci and streptococci, including strains that exhibit multidrug resistance.2 Resistance to streptogramins can develop through one of several mechanisms—alteration of the target site (the most common mechanism), active transport or efflux mediated by an ATP-binding protein and enzyme modification.3 The aims of the present study were to determine the antibiotic susceptibilities of strains of Staphylococcus aureus and Streptococcus spp. exhibiting intermediate susceptibility or resistance to quinupristin/dalfopristin and to investigate the clonal relatedness of these strains. The bacteria studied were identified from among a total of 2393 strains of S. aureus (574 of which were resistant to methicillin), 963 of S. pneumoniae and 486 of other Streptococcus spp. isolated in 24 university hospitals participating in the European SENTRY antimicrobial surveillance programme between April 1997 and February 1999. MICs of quinupristin/dalfopristin for the isolates were determined by a microbroth dilution method recommended by the NCCLS.4 The susceptibilities of strains for which the MICs of quinupristin/dalfopristin were ≥2 mg/L to several antibiotics were then determined by the same microbroth dilution method. The antibiotics were as follows: penicillin, oxacillin, ciprofloxacin, gentamicin, erythromycin, clindamycin, teicoplanin, vancomycin and the novel oxazolidinone, linezolid. In addition, the S. aureus strains were typed by a PFGE method described previously.5 Of the 3842 non-replicate strains submitted, 21 (0.9%) S. aureus isolates, one (0.1%) S. pneumoniae isolate and six (1.2%) other Streptococcus spp. isolates (comprising one strain each of Streptococcus mitis, Streptococcus oralis, Streptococcus bovis, Streptococcus porcinus, Streptococcus intermedius and Streptococcus sanguis) exhibited intermediate susceptibility or resistance to quinupristin/dalfopristin. Of the 21 S. aureus isolates, 18 were methicillin-resistant (MRSA) and three were methicillin-susceptible (MSSA); therefore 3.1% of MRSA isolates and 0.2% of MSSA isolates were non-susceptible to quinupristin/dalfopristin. Most (16) of the 21 S. aureus strains that were resistant to quinupristin/dalfopristin were referred from three hospitals in France, one of which contributed 14 strains. The remainder came from hospitals in Spain (three strains), Austria (one) and the UK (one). The single quinupristin/dalfopristin-resistant S. pneumoniae isolate was isolated in Germany and the six Streptococcus spp. isolates were from France (two strains), Austria (one), Italy (one), The Netherlands (one) and Turkey (one). Twenty-three (82%) of the 28 isolates were recovered from patients with bacteraemias, the remaining strains being isolated from patients with wound infections (three strains) or nosocomial pneumonias (two). The susceptibilities of the 28 strains are summarized in the Table. All 21 quinupristin/dalfopristin-resistant S. aureus isolates expressed the MLSB resistance phenotype and were resistant to penicillin and ciprofloxacin. The 18 MRSA isolates were also resistant to gentamicin (with 16 exhibiting high-level resistance) and five exhibited intermediate susceptibility to vancomycin (MICs 4 mg/L). The single quinupristin/dalfopristin-resistant S. pneumoniae isolate was susceptible to penicillin, vancomycin and clindamycin, but resistant to erythromycin; this strain therefore expressed the so-called M phenotype. Three of the six quinupristin/dalfopristin-resistant Streptococcus spp. isolates exhibited intermediate susceptibility or resistance to penicillin and all six expressed the MLSB resistance phenotype and exhibited reduced susceptibility to ciprofloxacin. All 28 strains were susceptible to linezolid (MICs 0.12–1 mg/L) (data not shown), an observation which suggests that it would have a role in the treatment of patients with infections caused by multidrug-resistant Gram-positive bacteria, including those resistant to quinupristin/dalfopristin. PFGE typing of the 21 S. aureus isolates revealed that 12 of the 14 strains referred from one French hospital were clonally related, as were two from a Spanish hospital. This is consistent with nosocomial transmission of these strains in the respective hospitals. The remaining French isolates (four of 16) and three of the five from other European countries were not clonally related. The results of this study indicate that the numbers of S. aureus and Streptococcus spp. (including S. pneumoniae) strains resistant to quinupristin/dalfopristin are currently very low in Europe. The majority of such organisms were isolated in France and this may have been the result of nosocomial spread of MRSA in one hospital. (Indeed, more than 95% of the MRSA strains isolated in that hospital exhibited resistance to multiple drugs, including quinupristin/dalfopristin.) Our results are in accord with those of a multicentre study carried out in 200 laboratories in the USA,1,2 in which 99% of S. aureus isolates, 98% of S. pneumoniae isolates and 97% of Streptococcus spp. isolates were shown to be susceptible to quinupristin/dalfopristin. Furthermore, a recent German surveillance study found no quinupristin/dalfopristin-resistant strains among 1359 staphylococci isolated from blood cultures.6 As streptogramin compounds have been used in France for more than 25 years, it is not entirely surprising that the incidence of resistance to quinupristin/dalfopristin among isolates from that country was higher than those among isolates from other countries. However, during a national survey in 1995, when 895 MRSA strains from 96 French non-university hospitals were studied, the MICs of quinupristin/dalfopristin for only 1.5% of these strains were ≥4 mg/L.7 Moreover, of the 37,775 S. aureus strains isolated from clinical specimens at Pitié-Salpêtrière Hospital between 1973 and 1996, quinupristin/dalfopristin resistance was found in ≤1% of MSSA isolates and ≤5% of MRSA isolates.8 In conclusion, resistance to quinupristin/dalfopristin among staphylococci and streptococci isolated in European university hospitals is still rare. None the less, as most of the resistant isolates were recovered from patients with bacteraemias and exhibited resistance to multiple other antibiotics, problems with treatment may arise in the future. A particular concern is that resistance to quinupristin/dalfopristin will increase as the drug is used more extensively. It is reassuring therefore that linezolid is currently active against all isolates resistant to quinupristin/dalfopristin. Finally, as most of the quinupristin/dalfopristin-resistant strains investigated in this study were isolated in 1998, ongoing surveillance to identify trends in resistance to this agent among Gram-positive bacteria must be a priority. MICs of quinupristin/dalfopristin and other antibiotics for S. aureus and Streptococcus spp. isolates exhibiting reduced susceptibility to quinupristin/dalfopristin MICs of quinupristin/dalfopristin and other antibiotics for S. aureus and Streptococcus spp. isolates exhibiting reduced susceptibility to quinupristin/dalfopristin We thank Marita Hautvast, Miriam Klootwijk, Carlijn Kusters and Stefan de Vaal for their expert technical assistance. This study was funded by Bristol-Myers Squibb Parmaceuticals via the SENTRY Antimicrobial Surveillance Program.