Prevalence of resistance to MLS antibiotics in 20 European university hospitals participating in the European SENTRY surveillance programme

Franz-Josef Schmitz*, Jan Verhoef, Ad C. Fluit and The Sentry Participants Group{dagger}

Eijkman- Winkler Institute for Clinical Microbiology, Utrecht University, Utrecht, The Netherlands


    Abstract
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 References
 
Macrolide, lincosamide and streptogramin (MLS) antibiotics are chemically distinct inhibitors of bacterial protein synthesis. Resistance to MLS antibiotics may be constitutive or inducible. The purpose of this study is to update our understanding of the prevalence of different forms of MLS resistance in Europe. The analysis of 3653 clinical pneumococcal, staphylococcal and enterococcal isolates exhibited an average percentage of 21.3% and 6.2% intermediate and high-level penicillin-resistant Streptococcus pneumoniae, 21.8% methicillin-resistant Staphylococcus aureus and 11% vancomycin-resistant Enterococcus faecium. Geographical differences in erythromycin and clindamycin resistance in isolates of S. pneumoniae and S. aureus strongly reflect geographical variations in susceptibility to penicillin and methicillin, respectively. A very narrow range of MICs was obtained with quinupristin/dalfopristin, with no S. pneumoniae, S. aureus and E. faecium isolate having an MIC of >4 mg/L, indicating a possible role of quinupristin/dalfopristin in the treatment of infections by multi-resistant Gram-positive bacteria.


    Introduction
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 References
 
Macrolide, lincosamide and streptogramin (MLS) antibiotics are chemically distinct inhibitors of bacterial protein synthesis. Macrolides can be divided into 14-, 15- and 16-membered lactone ring macrolides. Lincosamides are alkyl derivatives of proline and are devoid of a lactone ring. Streptogramin antibiotics are mixtures of naturally occurring cyclic peptide compounds. They are composed of two factors, A and B, with synergic inhibitory and bactericidal activity. 1

In 1956, a few years after introduction of erythromycin, resistance of staphylococci to this drug emerged. Since then, resistance to macrolides in staphylococci, pneumococci and enterococci has been reported world-wide.

Three different mechanisms of macrolide resistance have been described.

First, target modification is mediated by an rRNA erm methylase that alters a site in 23S rRNA common to the binding of macrolides, lincosamides and streptogramin B antibiotics. Modification of the ribosomal target confers cross-resistance to macrolides, lincosamides and streptogramin B antibiotics (MLSB resistant phenotype) and remains a frequent mechanism of resistance, although enzymatic modification and active efflux appears to be increasingly prevalent.1

Enzymes (EreA and EreB) that hydrolyse the lactone ring of the macrocyclic nucleus and phosphotransferases, which inactivate macrolides by introducing a phosphate on the 2'-hydroxyl group of the amino sugar, have been reported in Staphylococcus aureus. The presence of multicomponent macrolide efflux pumps in staphylococci (msrA, msrB) as well as an efflux system in streptococci (mefA, mefE) have also been documented. 1,2,3

Expression of MLS resistance in staphylococci may be constitutive or inducible. When expression is constitutive, the isolates are resistant to all macrolides, lincosamides and streptogramin B-type antibiotics. Streptogramin A-type antibiotics escape resistance, and synergism with streptogramin B-type antibiotics is retained. When expression is inducible, the isolates are resistant to 14- and 15-membered macrolides only. The 16-membered macrolides, the commercially available lincosamides, and the streptogramin antibiotics remain active. This dissociated resistance is due to differences in the inducing abilities of MLS antibiotics; only 14- and 15-membered macrolides are effective inducers of methylase synthesis.

MLS resistance in streptococci and enterococci can also be expressed constitutively or inducibly. However, unlike the case in staphylococci, various macrolides or lincosamides may act as inducers. Thus, in streptococci, whether inducible or constitutive, resistance by ribosomal methylation is crossed among macrolides, lincosamides and streptogramin B antibiotics. 1,2,3

Recent epidemiological surveys have shown that some erythromycin-resistant isolates of pneumococci and group A streptococci are not co-resistant to lincosamide and streptogramin antibiotics. Rather, clinical isolates have been shown to have the M-phenotype, namely, resistance to macrolides but susceptibility to lincosamide and streptogramin B antibiotics. These isolates contain the mefA or mefE gene coding for an efflux pump for 14- and 15-membered macrolides. 2,3

The purpose of this study is to update our understanding of the prevalence of different forms of MLS resistance in Europe and to compare the in-vitro activities of the macrolides azithromycin, clarithromycin, erythromycin, the lincosamide clindamycin and the streptogramin compound quinupristin/dalfopristin against 3653 routine clinical pneumococcal, staphylococcal and enterococcal bacterial isolates from 20 university hospitals participating in the European SENTRY programme.


    Material and methods
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 References
 
Bacterial isolates

The present study includes European clinical isolates from the initiation of the European SENTRY programme (April 1997–April 1998). The SENTRY programme is a longitudinal surveillance programme designed to monitor the predominant pathogens and antimicrobial resistance patterns of nosocomial and community acquired infections nationally and internationally. The monitored infections include bacteraemia (objective A), community acquired respiratory tract infections caused by fastidious organisms (objective B), nosocomial pneumonia (objective C), wound infections (objective D) and urinary tract infections (objective E).4

Isolates were referred to a regional reference laboratory located at the Eijkman-Winkler Institute for Clinical Microbiology, University Hospital Utrecht, from 20 hospitals in 12 European countries. As part of the SENTRY programme, participating centres were instructed to refer only the first 20 consecutive blood isolates of any species per month, and only 50 consecutive isolates from pneumonia, wound and urinary tract infections, respectively. Only one isolate per patient, which was considered clinically significant according to local criteria, was sent in. Each laboratory was encouraged to critically analyse coagulase-negative staphylococci (CNS) in the context of their clinical significance. Upon receipt, isolates were subcultured onto blood agar to ensure purity. Isolate identity was confirmed if necessary using a Vitek system (bioMerieux, Lyon, France). All isolates received were immediately stored at -70°C until studied further.

The staphylococcal, enterococcal and Streptococcus pneumoniae isolates tested had the following origin:

S. aureus: 60% objective A, 15% objective C, 23% objective D, 2% objective E;

CNS: 92% objective A, 6% objective D, 2% objective E;

S. pneumoniae: 19% objective A, 70% objective B, 11% objective C 8%;

Enterococcus faecalis: 66% objective A, 6% objective C, 12% objective D, 16% objective E;

Enterococcus faecium: 82% objective A, 3% objective C, 7% objective D, 8% objective E.

Participating hospitals

These included Austria (Krankenhaus der Elisabethinen, Linz), Belgium (Hôpital Erasme, Brussels), France (Hôpital St Joseph, Paris; Hôpital de la Pitié-Salpêtrière, Paris; Hôpital Eduard Herriot, Lyon; A. Calmette Hôpital, Lille), Germany (University Hospital Freiburg, Freiburg; University Hospital Düsseldorf, Düsseldorf), Greece (National University of Athens, Athens), Italy (University Hospital of Genoa, Genoa; University Hospital of Rome, Rome), The Netherlands (University Hospital Utrecht, Utrecht), Poland (Jagiellonian University Hospital, Cracow; University Hospital Warsaw, Warsaw), Portugal (University Hospital of Coimbra, Coimbra), Spain (University Hospital of Sevilla, Sevilla; Hospital Ramon y Cajal, Madrid; Hospital de Bellvitge, Barcelona), Switzerland (CHUV, Lausanne) and the UK (St Thomas's Hospital Medical School, London).

Susceptibility testing

Antimicrobial susceptibility testing of isolates was performed by reference broth microdilution methods according to NCCLS recommended guidelines. 5 Azithromycin, clarithromycin, erythromycin, clindamycin and quinupristin/ dalfopristin were obtained from the respective manufacturers.

Cation-adjusted Mueller- Hinton broth was used as the growth medium throughout the study (Dade International, Sacramento, CA, USA). The final bacterial inoculum concentration was approximately 5 x 105 cfu/mL. Trays were incubated for 20–24 h at 35°C in ambient air before determining MIC values. Microdilution trays were purchased from MicroScan (Sacramento, CA, USA). Quality control was performed by testing S. aureus ATCC 29213, S. pneumoniae ATCC 49619 and E. faecalis ATCC 29212. The quality control organisms were tested on each day of testing. NCCLS-defined breakpoints were used to interpret MIC data in subsequent analyses. 5


    Results
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 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 References
 
Streptococcus pneumoniae

Among the 697 isolates of S. pneumoniae tested in the present study, 72.6% were susceptible to penicillin, 21.2 were intermediate and 6.2% were highly penicillin resistant (MICs >=2 mg/L) (Tables I and II). Individual rates of resistance among the university hospitals are listed in Table II. The combined percentages of intermediate and resistant isolates varied between 7% and 55%. For this analysis, hospitals 11 and 1 have been excluded, as these two contributed only one and two isolates, respectively. In general, high percentages of intermediate and resistant isolates were observed in Portugal (31%), France (41–55%), Spain (45–55%) and Greece (50%). In contrast, low combined resistant rates were observed in Austria (0%), Germany (12–13%), Switzerland (12%) and the UK (14%).


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Table I. Antibacterial activities of macrolides, clindamycin and quinupristin/dalfopristin against 3649 pneumococcal, staphylococcal and enterococcal isolates from 20 European university hospitals participating in the European SENTRY surveillance programme
 

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Table II. Distribution of erythromycin and clindamycin susceptibility in S. pneumoniae isolates from 20 European university hospitals participating in the European SENTRY programme (data are expressed in percentage of isolates)
 
Although there were subtle differences in the activity of the three macrolides tested against S. pneumoniae when results were based on MIC results (Table I), comparisons based on calculations of percentages of susceptible, intermediate and resistant isolates indicated essential equivalence among these compounds.

As seen in Tables I and II, there was a clear relationship between penicillin activity and the activity of macrolides and clindamycin. In all cases, resistance to these agents was more common among penicillin-intermediate isolates than among penicillin-susceptible isolates, and most common among high-level penicillin-resistant organisms. Overall, the rate of erythromycin resistance in penicillin-susceptible isolates was around 8%, but the rate increases to 31% in intermediately resistant pneumococci and to 56% in high-level penicillin-resistant isolates.

Geographical differences in erythromycin and clindamycin susceptibility in isolates of S. pneumoniae reflect geographical variations in susceptibility to penicillin. Those countries with a higher prevalence of penicillin-intermediate and -resistant isolates, such as France and Spain, show higher levels of erythromycin and clindamycin resistance, although intra-country variations in the prevalence of such resistance phenotypes occur. Nevertheless, the relationship between the prevalence of penicillin resistance and macrolide-lincosamide resistance remains (Table II).

The so-called M-phenotype (macrolide-resistant, clindamycin-susceptible) was observed in 2.3% of penicillin- susceptible, 4.1% of penicillin-intermediate and 6.2% of penicillin-resistant S. pneumoniae isolates.

A very narrow range of MICs was obtained with the quinupristin/dalfopristin combination, with no organism having an MIC of >4 mg/L. MIC50 and MIC90 values were 0.5 and 1.0 mg/L, respectively, irrespective of penicillin susceptibility of organisms tested.

Staphylococcus aureus

A total of 1554 S. aureus isolates were referred during the study period. Of these S. aureus isolates 1212/1554 (78%) were methicillin susceptible; 380/909 (42%) of all CNS isolates were susceptible to methicillin (Table I). Predictable geographical variation in the rates of methicillin susceptibility occurred amongst S. aureus isolates between the 20 hospitals studied (Table III).


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Table III. Distribution of erythromycin and clindamycin susceptibility in methicillin-susceptible and methicillin-resistant S. aureus isolates from 20 European university hospitals participating in the European SENTRY programme (data are expressed in percentage of isolates)
 
Of the S. aureus isolates, 61% were susceptible to erythromycin, and 73% to clindamycin (Tables I and III). The percentage of methicillin-susceptible S. aureus (MSSA) which showed susceptibility to erythromycin was 19.7 times higher compared with methicillin-resistant S. aureus (MRSA) isolates (Tables I and III). Whereas 90.3% of the MSSA were susceptible to clindamycin, only 10.6% of the MRSA exhibited susceptibility.

Ninety-three per cent of the macrolide-resistant MRSA isolates and 44% of the macrolide-resistant MSSA isolates displayed a constitutive MLSB resistance phenotype. The rest of the macrolide-resistant S. aureus isolates had an inducible MLS B resistance phenotype

Of the CNS isolates, 37% were susceptible to erythromycin and 59% to clindamycin (Table I). In contrast to S. aureus, the differences in the percentage of macrolide and lincosamide susceptibility between methicillin- resistant CNS (MRCNS) and methicillin-susceptible CNS (MSCNS) were less pronounced. The percentage of MSCNS showing susceptibility to erythromycin was 2.5 times higher, and for clindamycin susceptibility 1.8 times higher compared with MRCNS isolates.

Overall MSCNS are more resistant to erythromycin and clindamycin than MSSA, whereas MRCNS show less resistance compared with MRSA isolates (Table I). Unlike S. aureus in CNS the association between methicillin resistance and erythromycin and clindamycin resistance is not as pronounced as for S. aureus.

Geographical differences in erythromycin and clindamycin resistance in isolates of S. aureus strongly reflect geographical variations in susceptibility to methicillin. Those countries with a higher prevalence of MRSA, such as Belgium, France, Italy, Portugal and Spain, show higher levels of resistance, although intra-country variations in the prevalence of such resistance phenotypes occur (Table III).

Quinupristin/dalfopristin exhibited good in-vitro activities against S. aureus and CNS, with MIC90 values of 0.25 mg/L for MSSA and MSCNS, 0.25 mg/L for MRCNS and 1 mg/L for MRSA (Table I). None of the staphylococci tested exhibited MIC values >4 mg/L. No differences in the MIC50 and MIC90 values were observed between S. aureusisolates, either MSSA or MRSA, with a constitutive or an inducible MLSB resistance phenotype.

Enterococcus spp.

Ten of 90 E. faecium isolates tested (11%) exhibited vancomycin resistance, whereas none of the E. faecalis isolates tested was vancomycin resistant. The vancomycin-resistant E. faecium isolates were isolated in Portugal (9) and Italy (1), and exhibited complete cross resistance to erythromycin and clindamycin (Table IV).


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Table IV. Distribution of erythromycin and clindamycin susceptibility in E. faecalis and E. faecium isolates from 20 European university hospitals participating in the European SENTRY programme (data are expressed in percentage of isolates)
 
Only 13.3% and 8.6% of all enterococcal isolates (n = 493) were fully susceptible to erythromycin and clindamycin. E. faeciumisolates were less susceptible to erythromycin than were E. faecalis isolates whereas the opposite was true for clindamycin susceptibility (Table I and IV).

Quinupristin/dalfopristin was ineffective against E. faecalis isolates, whereas none of the E. faecium isolates had an MIC of >4 mg/L. MIC50 and MIC 90 values were 1 and 4 mg/L, respectively.


    Discussion
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 References
 
Streptococcus pneumoniae

Until the 1970s, S. pneumoniae infections were successfully treated with ß-lactam antibiotics. Since then, however, increasing resistance to penicillin has been reported on a world-wide scale, with 10–50% of S. pneumoniae isolates now being non-susceptible to penicillin.6

Among the 697 isolates of S. pneumoniae tested, 72.6% were susceptible to penicillin, 21.2% were intermediate and 6.2% were highly penicillin resistant. In general, high percentages of intermediate and resistant isolates were observed in Portugal, France, Spain and Greece. In contrast, low combined resistant rates were observed in Austria, Germany, Switzerland and the UK. Baquero et al.6 similarly noted high resistance rates in Spain, France and Portugal.

There was a clear relationship between penicillin activity and the activity of macrolides and clindamycin. Resistance to these agents was more common among penicillin- intermediate isolates than among penicillin-susceptible isolates, and most common among high-level penicillin-resistant organisms. Baquero et al.6 described current levels of macrolide resistance of the order of up to 10% in penicillin-susceptible isolates and 30–40% in penicillin non-susceptible isolates. But as with other resistance rates, this varies widely from country to country. Nevertheless, a major problem is the emergence of multiple-resistant isolates of S. pneumoniae. The correlation between the local prevalence of penicillin and macrolide resistance suggests that a relatively low number of clones with evolving penicillin resistance have acquired macrolide resistance determinants.6,7 This may indicate that high-level resistance has evolved on certain intermediately resistant clones which harboured macrolide resistance determinants. As different clones are involved in different types of infection, this may explain why the rates of both penicillin and macrolide resistance tend to be significantly higher in isolates obtained from middle ear effusion or sputum than in blood isolates. 6

The so-called M-phenotype was observed in 2.3% of penicillin-susceptible, 4.1% of penicillin-intermediate and 6.2% of penicillin-resistant S. pneumoniae isolates. Sutcliffe et al. have described an efflux system for erythromycin in these M isolates which is apparently distinct from the efflux system in staphylococci. 3 Information covering this phenotype is limited because of the assumption that erythromycin resistance implies co-resistance to clindamycin. The discovery of the M-phenotype has led to suggestions that lincosamides may have an emerging role in the therapy of pneumococcal infections, especially in those caused by drug-resistant S. pneumoniae. This concept is supported by the acceptable bioavailability of clindamycin by the oral route and its good penetration into many tissues such as subcutaneous tissue, bone and gingival crevicular fluid.8 Further studies of the incidence of cross-resistance to clindamycin among erythromycin-resistant pneumococci are warranted as we seek therapeutic alternatives for infections caused by multiple-resistant S. pneumoniae.

Interpretive criteria have not been established for the combination quinupristin/dalfopristin versus S. pneumoniae; however, a very narrow range of MICs was obtained with this combination, with no organism having an MIC of >4 mg/L. Barry et al.proposed the following provisional breakpoints for dilution tests with quinupristin/ dalfopristin: susceptible, MIC <=1.0 mg/L; intermediate, MIC = 2.0 mg/L; resistant, MIC >=4 mg/L. Those interpretative criteria are provisional, pending clinical experience and further study of more fastidious species.9 Decreased susceptibility to streptogramin combinations in S. pneumoniae and other Gram-positive bacteria can occur by one of several resistance mechanisms (modified target, drug inactivation, active efflux, or block of permeases), but this is rare.10,11

Tarasi et al. tested 217 pneumococcal isolates, including 89 intermediate and 111 high-level penicillin-resistant isolates. None of the isolates showed resistance to quinupristin/dalfopristin, with an MIC50 of 0.25 mg/L and an MIC90 of 0.5 mg/L. Because of the known importance of bactericidal activity for successful therapy of pneumococcal meningitis, a number of experiments were performed by Tarasi et al. to test the killing activity of quinupristin/ dalfopristin both in vitro and in a rabbit model of experimental meningitis.12 In summary, in those experiments quinupristin/dalfopristin was an effective antibacterial agent.

On the basis of in-vitro and in-vivo experiments, quinupristin/dalfopristin might be sometimes an alternative for infections caused by S. pneumoniae,especially by multiple-resistant isolates.

Staphylococcus aureus

The percentage of MSSA that showed susceptibility to erythromycin was 19.7 times higher compared with MRSA isolates. Whereas 90.3% of the MSSA were susceptible to clindamycin, only 10.6% of the MRSA exhibited susceptibility. The percentage of MSCNS showing susceptibility to erythromycin was 2.5 times higher and for clindamycin susceptibility 1.8 times higher compared with MRCNS isolates.

Cross-resistance between methicillin and macrolides- lincosamides has been described by others.4 Extensive use of the older macrolide compounds has led to widespread resistance.13 Almost all MRSA are resistant to erythromycin and the newer 14- and 15-membered macrolides. The 16-membered macrolides, on the other hand, are active against staphylococci in which resistance to erythromycin is inducible. Whether this extends to clinical effectiveness remains to be determined and, at present, macrolides cannot be considered as effective therapies, especially for MRSA infection.13

Resistance, and the emergence of resistance to clindamycin during therapy, is common, especially in MRSA, particularly if the isolate is already resistant to erythromycin. The drug has been used successfully in treatment of hip and bone infections, but, because of the rapid emergence of resistance to clindamycin, the drug is never the first drug of choice, even for susceptible isolates.13

Quinupristin/dalfopristin exhibited good in-vitro activities against S. aureus and CNS. None of the staphylococci tested exhibited MIC values >4 mg/L. This new injectable streptogramin is composed of a streptogramin B, quinupristin, and a streptogramin A, dalfopristin, combined in a 30:70 ratio. Both compounds bind to the 23S RNA of the 50S ribosomal subunit. They act synergically to inhibit protein synthesis.

The in-vitro bactericidal activity of quinupristin/dalfopristin against S. aureus seems to be affected by the macrolide-resistance phenotype, and this may account for the interstudy variation in its MBC and kill kinetics.14 MRSA appeared to be less susceptible to the bactericidal action of quinupristin/dalfopristin than MSSA, which is in agreement with the different MIC90 values found in this study. In the present investigation, no difference in MIC50 and MIC90 values was found between S. aureus isolates, either MSSA or MRSA, with a constitutive or an inducible MLSB resistance phenotype. In a comparison of the bactericidal activity and kill kinetics of quinupristin/dalfopristin against 13 constitutively resistant and 10 inducibly resistant isolates of S. aureus, approximately 50% of constitutively resistant isolates demonstrated MBCs >=4 mg/L or compromised bactericidal susceptibility. 15 The rapid bactericidal action of quinupristin/dalfopristin against erythromycin-susceptible or inducibly resistant isolates of MRSA, contrasting with its compromised bactericidal activity against constitutively resistant isolates, has been confirmed in an in-vivo animal model of endocarditis.16 However, the bactericidal action of quinupristin/dalfopristin could be restored to a level similar to that of vancomycin by co-administration of dalfopristin, thereby maintaining serum concentrations of the component with the shorter half-life. Thus, quinupristin/dalfopristin might be a promising alternative to vancomycin against MRSA, provided that pharmacokinetic parameters are adjusted to afford prolonged levels of both its constituents in serum. The misleading global kinetics of quinupristin/dalfopristin might also explain previous failures of the drug to cure experimental MRSA endocarditis.17

Further in-vitro and in-vivo studies are needed to evaluate the role of quinupristin/dalfopristin, alone or in various combinations, in the treatment of staphylococcal infections as well as the possible emergence of resistance during therapy. Additionally, further work is required to determine the possible contribution of genetic resistance determinants to the in-vitro and in-vivo activity of quinupristin/ dalfopristin.

Enterococcus spp.

Over the past few years there has been a dramatic increase in the incidence of nosocomially acquired enterococci, particularly E. faecium resistant to vancomycin, especially in the USA.10 Ten of 90 E. faecium isolates tested exhibited vancomycin resistance, and none of the E. faecalis isolates tested was vancomycin resistant.

Only 13.3% and 8.6% of all enterococcal isolates were fully susceptible to erythromycin and clindamycin. Thus, macrolides and lincosamides cannot be considered as real therapeutic options in enterococcal infections.13

Quinupristin/dalfopristin was ineffective against E. faecalis isolates, whereas no E. faecium isolate showed an MIC of >4 mg/L.

The slowly bactericidal effects of quinupristin/dalfopristin on E. faecium isolates with vancomycin resistance and concurrent macrolide resistance has to be emphasized. 18 Only those enterococcal isolates with erythromycin-susceptible test results would be expected to be rapidly killed by quinupristin/dalfopristin.18 Physicians attempting to use quinupristin/dalfopristin for a bactericidal action should probably seek additional testing of macrolide agents to guide therapy within available indications. Such a procedure may limit the occurrence of resistance emerging on quinupristin/dalfopristin chemotherapy. 19

As quinupristin/dalfopristin has been shown to be active against E. faecium isolates in vitro and in vivo,20,21 the clinical potential of this antibiotic might lie in the treatment of infections caused by enterococci resistant to macrolides, lincosamides or vancomycin. Serious infections with vancomycin-resistant E. faecium (VREF) isolates have no proven effective antimicrobial therapy. Linden et al. compared the clinical and bacteriological outcomes of 20 patients with VREF bacteraemia treated with quinupristin/ dalfopristin with a historical cohort of 42 patients with VREF. Quinupristin/dalfopristin demonstrated in-vitro bacteriostatic activity against all 20 initial VREF blood isolates. The rate of recurrent VREF bacteraemia as well as VREF-associated mortality was significant lower in the quinupristin/dalfopristin group. 21 Quinupristin/dalfopristin may be a useful agent for the therapy of serious VREF infection. Several other investigators have documented in-vitro and in-vivo activity of quinupristin/dalfopristin against E. faecium isolates. 20,21 However, in parallel with the possible contribution of genetic resistance determinants on the in-vitro and in-vivo activity of quinupristin/ dalfopristin in S. aureus, the activity of quinupristin/ dalfopristin in E. faecium seems to be influenced by the MLSB resistance phenotype.22 Fantin et al. observed a reduced activity of quinupristin/dalfopristin against E. faecium with inducible MLSB resistance.22

The published clinical results after treatment of E. faecium infections are promising, 20,21 but should be considered as preliminary data and thus interpreted with caution.

In summary, the analysis of 3653 clinical pneumococcal, staphylococcal and enterococcal isolates exhibited an average percentage of 21.3% and 6.2% intermediate and high-level penicillin-resistant S. pneumoniae, 21.8% MRSA, 58.2% MRCNS and 11% VREF. Geographical differences in erythromycin and clindamycin resistance in isolates of S. pneumoniaeand S. aureus strongly reflect geographical variations in susceptibility to penicillin and methicillin, respectively. A very narrow range of MICs was obtained with quinupristin/dalfopristin, with no S. pneumoniae, S. aureus or E. faecium isolate having an MIC of >4 mg/L. Thus, quinupristin/dalfopristin might be useful in the treatment of multidrug resistant Gram-positive bacteria.


    Acknowledgments
 
We thank Marita Hautvast, Miriam Klootwijk, Carlijn Kusters and Stefan de Vaal for their expert technical assistance. This work was funded by Bristol-Myers Squibb Pharmaceuticals via the SENTRY Antimicrobial Surveillance Programme.


    Notes
 
* Correspondence address. Institute for Medical Microbiology and Virology, Henrich-Heine-Universität Düsseldorf, Universitätsstrasse 1, Geb. 22.21, 40225 Düsseldorf, Germany. Tel and Fax: +49-2132-72040. Back

{dagger} The SENTRY participants group consists of: Professor Helmut Mittermayer, Professor Marc Struelens, Professor Jacques Acar, Professor Vincent Jarlier, Professor Jerome Etienne, Professor Rene Courcol, Professor Franz Daschner, Professor Ulrich Hadding, Professor Nikos Legakis, Professor Gian-Carlo Schito, Professor Carlo Mancini, Professor Piotr Heczko, Professor Waleria Hyrniewicz, Professor Dario Costa, Professor Evilio Perea, Professor Fernando Baquero, Dr Rogelio Martin Alvarez, Professor Jacques Bille and Professor Gary French. Back


    References
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 References
 
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Received 21 October 1998; returned 30 December 1998; revised 16 February 1999; accepted 4 March 1999