Clinical Microbiology and Infection
Volume 5, Issue 8 pp. 488-495
Free Access

In vitro activity of quinupristin/dalfopristin against selected bacterial pathogens isolated in Italy

Anna Marchese, 

Anna Marchese

Institute of Microbiology, University of Genoa, Genoa, Italy

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Eugenio A. Debbia, 

Corresponding Author

Eugenio A. Debbia

Institute of Microbiology, University of Genoa, Genoa, Italy

Corresponding author and reprint requests: Eugenio A. Debbia, Institute of Microbiology, University of Genoa, Largo Rosanna Benzi, 10, 16132 Genoa, Italy Tel: +39 10 3537655 Fax: +39 10 504837 E-mail: [email protected]Search for more papers by this author
Gian Carlo Schito, 

Gian Carlo Schito

Institute of Microbiology, University of Genoa, Genoa, Italy

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First published: 27 October 2008
https://doi.org/10.1111/j.1469-0691.1999.tb00178.x

Abstract

Objectives: To evaluate the activity of quinupristin/dalfopristin, a new injectable streptogramin, against 732 clinical strains recently isolated in Italy.

Methods: Susceptibility tests were performed according to NCCLS-guided MIC methodology. Pathogens included in the evaluation included 108 Staphylococcus aureus isolates, 124 coagulase-negative staphylococcal isolates, 158 Streptococcus pyogenes isolates, 30 Streptococcus agalactiae isolates, 30 β-hemolytic streptococcal isolates, 18 Streptococcus sanguis isolates, 80 Streptococcus pneumoniae isolates, 69 Enterococcal isolates, 40 Haemophilus influenzae isolates, 30 Moraxella catarrhalis isolates and, finally, 30 Gram-positive and 25 Gram-negative anaerobes.

Results: Quinupristin/dalfopristin inhibited Staphylococcus aureus and other Staphylococcus spp., irrespective of their oxacillin or erythromycin resistance phenotypes. Similarly, streptococci were fully inhibited by quinupristin/dalfopristin. Enterococcus faecalis was not included in the spectrum of this streptogramin, while isolates of Enterococcus faecium were inhibited by the new compound. Respiratory pathogens such as H. influenzae and M. catarrhalis were inhibited by quinupristin/dalfopristin as well as all Gram-negative anaerobes tested.

Conclusions: These findings suggest a putative role for quinupristin/dalfopristin in the empirical treatment of severe nosocomial and community-acquired infections caused by pathogens often displaying resistance to multiple antibiotics. This drug may provide an alternative to glycopeptide compounds.

INTRODUCTION

Loss of susceptibility to previously effective drugs in Gram-positive organisms poses major therapeutic problems globally [1–4]. In particular, this threat is represented by staphylococcal organisms, the etiologic agents dominating nosocomial infections, which, at least in Italy, express a high level of methicillin and associated multiple resistance. Recent reports have suggested that staphylococcal species are evolving towards reduced susceptibility to vancomycin, the drug of choice in most infections [5–7].

In Enterococcus, aminoglycoside resistance preventing synergistic interactions with penicillin, and glycopeptide resistance, are established in some regions of the world [1], while in Streptococcus pyogenes, increased resistance to drugs such as the macrolides, the preferred alternative treatment to penicillin, is posing therapeutic problems [8]. The viridans group of screptococci, while becoming increasingly important as a cause of bacteremia in the immunocompromised host, is becoming increasingly refractory to penicillin [9]. Similarly, the incidence of penicillin-resistant and multiresistant pneumococci is increasing worldwide [10]. Increasing resistance is also apparent in community-acquired Gram-negative organisms associated with respiratory tract infections, such as Haemophilus influenzae and Moraxella catarrhalis, in which rates of ampicillin resistance due to synthesis of β-lactamases are often in excess of 30% [11] and 90% [12] respectively.

The need for alternative drugs capable of overcoming the widespread resistance presented by primary nosocomial and community-acquired Gram-positive and respiratory Gram-negative pathogens is paramount. Quinupristin/dalfopristin (Synercid, RP 59500), a new injectable streptogramin, has shown promising bactericidal activity in in vitro tests on most refractory Gram-positive aerobic and anaerobic organisms analyzed thus far [13–15]. Its spectrum also encompasses Gram-negative respiratory pathogens and anaerobes [14, 15].

Quinupristin/dalfopristin will soon be introduced for clinical usage in Italy, a country whose unique patterns of antibiotic prescription [16, 17] have probably contributed to an epidemiology of resistant pathogens that differ somewhat from that in other European nations [18]. For this reason, and in order to investigate the efficacy and potency of this new drug on clinical isolates representing a specific resistance phenotype, we undertook this ad hoc investigation, performed during 1996–97.

Materials and Methods

Bacterial strains

Recently isolated non-duplicate nosocomial and community-acquired pathogens were included in the study. Numbers of organisms studied and specific resistance phenotypes are shown in Tables 1–7.

Table 1. In vitro activity of quinupristin/dalfopristin and other drugs against 232 Staphylococcus strains
Organism
(number tested)		 Antibiotic Range
(mg/L)		 MIC50
(mg/L)		 MIC90
(mg/L)		 % susceptible
at recommended
breakpointa
Staphylococcus aureus
oxaS (38)		 Quinupristin/dalfopristin 0.06–0.5 0.12 0.25 100
Clindamycin 0.25–0.5 0.5 0.5 100
Erythromycin 0.06 to >128 0.25 0.25 89.4
Oxacillin 0.12–2 0.25 0.5 100
Ciprofloxacin 0.12–64 0.25 0.5 97.3
Teicoplanin 0.25–2 0.5 1 100
Vancomycin 0.5–1 0.5 0.5 100
Staphylococcus auteus
oxaR (70)		 Quinupristin/dalfopristin 0.12–1 0.5 0.5 100
Clindamycin 0.25 to >128 128 >128 30
Erythromycin 0.12 to >128 128 >128 20
Oxacillin 8 to >128 128 >128 0
Ciprofloxacin 8–64 16 16 12.8
Teicoplanin 0.25–4 1 2 100
Vancomycin 0.5–1 0.5 0.5 100
CNS
oxaS (68)		 Quinupristin/dalfopristin 0.06–0.5 0.12 0.5 100
Clindamycin 0.06 to >128 0.25 >128 75
Erythromycin 0.12 to >128 0.25 >128 75
Oxacillin 0.06–2 0.25 2 100
Ciprofloxacin 0.06–64 0.25 8 75
Teicoplanin 0.12–2 1 2 100
Vancomycin 0.25–2 1 2 100
CNS
oxaR (56)		 Quinupristin/dalfopristin 0.12–0.5 0.12 0.5 100
Clindamycin 0.12 to >128 >128 >128 25
Erythromycin 0.12 to >128 >128 >128 21.4
Oxacillin 4 to >128 128 >128 0
Ciprofloxacin 0.12–64 16 32 16
Teicoplanin 0.5–8 2 8 100
Vancomycin 1–2 2 2 100
  • oxaS, oxacillin susceptible; oxaR, oxacillin resistant; CNS, coagulase-negative staphylococci.
  • aAccording to NCCLS [19] guidelines, Barry et al [37] and Tenover and Baker [38].
Table 2. In vitro activity of quinupristin/dalfopristin and other drugs against 158 Streptococcus pyogenes strains
Organism
(number tested)		 Antibiotic Range
(mg/L)		 MIC50
(mg/L)		 MIC90
(mg/L)		 % susceptible
at recommended
breakpointa
Streptococcus pyogenes
eryS (68)		 Quinupristin/dalfopristin ≤0.06 ≤0.06 ≤0.06 100
Penicillin ≤0.06 ≤0.06 ≤0.06 100
Ceftriaxone ≤0.06 ≤0.06 ≤0.06 100
Erythromycin ≤0.06–0.125 0.125 0.125 100
Ciprofloxacin 0.25 0.25 0.25 100
Vancomycin 0.25 0.25 0.25 100
Streptococcus pyogenes
eryR (C) (30)		 Quinupristin/dalfopristin ≤0.06–0.25 ≤0.06 0.125 100
Penicillin ≤0.06 ≤0.06 ≤0.06 100
Ceftriaxone ≤0.06 ≤0.06 ≤0.06 100
Erythromycin 64 to >64 >64 >64 0
Ciprofloxacin 0.25–0.5 0.25 0.25 100
Vancomycin 0.25 0.25 0.25 100
Streptococcus pyogenes
eryR (I) (30)		 Quinupristin/dalfopristin ≤0.06–0.125 0.125 0.125 100
Penicillin ≤0.06 ≤0.06 ≤0.06 100
Ceftriaxone ≤0.06 ≤0.06 ≤0.06 100
Erythromycin 32 to >64 >64 >64 0
Ciprofloxacin 0.25 0.25 0.25 100
Vancomycin 0.25 0.25 0.25 100
Streptococcus pyogenes
eryR (M) (30)		 Quinupristin/dalfopristin ≤0.06–0.125 ≤0.06 ≤0.06 100
Penicillin ≤0.06 ≤0.06 ≤0.06 100
Ceftriaxone ≤0.06 ≤0.06 ≤0.06 100
Erythromycin 16–32 16 16 0
Ciprofloxacin 0.125–0.25 0.25 0.25 100
Vancomycin 0.25 0.25 0.25 100
  • eryS, erythromycin susceptible; eryR, erythromycin resistant. Phenotypes: C, constitutive; I, inducible: M. efflux [39].
  • aAccording to NCCLS [19] guidelines, Barry et al [37] and Tenover and Baker [38].
Table 3. In vitro activity of quinupristin/dalfopristin and other drugs against 78 β-hemolytic Streptococcus strains and Streptococcus sanguis
Organism
(number tested)		 Antibiotic Range
(mg/L)		 MIC50
(mg/L)		 MIC90
(mg/L)		 % susceptible
at recommended
breakpointa
Streptococcus agalatiae
(30)		 Quinupristin/dalfopristin 0.25 0.25 0.25 100
Erythromycin 0.125–0.25 0.25 0.25 100
Penicillin ≤0.06 ≤0.06 ≤0.06 100
Ceftriaxone ≤0.06 ≤0.06 ≤0.06 100
Vancomycin 0.25–0.5 0.5 0.5 100
Ciprofloxacin 0.5–1 1 1 100
Streptococcus spp. (C,G,F) Quinupristin/dalfopristin 0.25–1 0.5 1 100
Erythromycin ≤0.06–0.25 0.125 0.25 100
(30) Penicillin ≤0.06–0.125 ≤0.06 0.125 100
Ceftriaxone ≤0.06–0.125 ≤0.06 0.125 100
Vancomycin 0.5–1 1 1 100
Ciprofloxacin 0.5–1 1 1 100
Streptococcus sanguis
(18)		 Quinupristin/dalfopristin 0.5–1 1 1 100
Erythromycin ≤0.06 ≤0.06 ≤0.06 100
Penicillin ≤0.06 ≤0.06 ≤0.06 100
Ceftriaxone ≤0.06 ≤0.06 ≤0.06 100
Vancomycin 0.5 0.5 0.5 100
Ciprofloxacin 1 1 1 100
  • β-Hemolytic Streptococcus isolates C 6, G 18, and F 6.
  • See also 1–7.
  • aAccording to NCCLS [19] guidelines, Barry et al [37] and Tenover and Baker [38].
Table 4. In vitro activity of quinupristin/dalfopristin and other drugs against 70 Streptococcus pneumoniae strains
Organism
(number tested)		 Antibiotic Range
(mg/L)		 MIC50
(mg/L)		 MIC90
(mg/L)		 % susceptible
at recommended
breakpointa
Streptococcus pneumoniae
penS (40)		 Quinupristin/dalfopristin 0.5–1 0.5 1 100
Penicillin ≤0.007–0.015 ≤0.007 ≤0.007 100
Ceftriaxone ≤0.125 ≤0.125 ≤0.125 100
Ciprofloxacin 0.5–2 1 2
Erythromycin ≤0.125 ≤0.125 ≤0.125 100
Vancomycin ≤0.125–0.25 ≤0.125 0.25 100
Streptococcus pneumoniae
penI (10)		 Quinupristin/dalfopristin 0.5–1 1 1 100
Penicillin 0.12–1 0.12 1 0
Ceftriaxone ≤0.12–0.5 0.5 0.5 100
Ciprofloxacin 1–4 2 4 -b
Erythromycin 0.25 to >128 128 >128 20
Vancomycin ≤0.125–0.25 ≤0.125 0.25 100
Streptococcus pneumoniae
penR (10)		 Quinupristin/dalfopristin 0.5–1 1 1 100
Penicillin 2–4 2 2 0
Ceftriaxone 0.5–1 0.5 0.5 60
Ciprofloxacin 0.5–4 2 4 -b
Erythromycin 0.5 to >128 0.5 128 50
Vancomycin ≤0.125–0.25 0.25 0.25 100
Streptococcus pneumoniae
eryR (10)		 Quinupristin/dalfopristin 0.5–1 0.5 1 100
Penicillin ≤0.007–0.06 ≤0.007 0.06 100
Ceftriaxone ≤0.125 ≤0.125 ≤0.125 100
Ciprofloxacin 1–2 1 2
Erythromycin 8–64 64 64 0
Vancomycin ≤0.125–0.25 ≤0.125 0.25 100
  • penS, penicillin susceptible; penl, penicillin intermediate; penR, penicillin resistant; eryR, erythromycin resistant.
  • aAccording to NCCLS recommended guidelines [19], Barry et al [37] and Tenover and Baker [38].
  • bNo breakpoint available in NCCLS guidelines.
Table 5. In vitro activity of quinupristin/dalfopristin and other drugs against 69 enterococci
Organism
(number tested)		 Antibiotic Range
(mg/L)		 MIC50
(mg/L)		 MIC90
(mg/L)		 % susceptible
at recommended
breakpointa
Enterococcus faecalis
vanS (40)		 Quinupristin/dalfopristin 0.25–8 4 8 5
Gentamicin 8 to >500 16 >500 80
Ciprofloxacin 0.5–64 1 32 75
Erythromycin 0.06 to >128 64 >128 2.5
Doxycycline 0.12–32 16 32 22.5
Vancomycin 0.5–4 1 4 100
Teicoplanin 0.06–1 0.25 0.5 100
Enterococcus faecalis
vanR (5)		 Quinupristin/dalfopristin 4–8
Gentamicin 8 to >500
Ciprofloxacin 8–64
Erythromycin 64 to >128
Doxycycline 16–32
Vancomycin 128–256
Teicoplanin 16–128
Enterococcus faecium
vanS (17)		 Quinupristin/dalfopristin 0.12–4 0.5 1 82
Gentamicin 2 to >500 16 >500 70
Ciprofloxacin 1 to >128 4 128 41
Erythromycin 0.5 to >128 128 >128 0.05
Doxycycline 0.06–32 8 16 41
Vancomycin 0.5–4 1 2 100
Teicoplanin 0.12–0.5 0.25 0.5 100
Enterococcus faecium
vanR (7)		 Quinupristin/dalfopristin 0.25–8
Gentamicin 2 to >500
Ciprofloxacin 1–64
Erythromycin 2 to >128
Doxycycline 8–32
Vancomycin 256
Teicoplanin 64–256
  • vanS, vancomycin susceptible; vanR, vancomycin resistant.
  • aAccording to NCCLS recommended guidelines [19], Barry et al [37] and Tenover and Baker [38].
Table 6. In vitro activity of quinupristin/dalfopristin and other drugs against 70 respiratory Gram-negative aerobes
Organism
(number tested)		 Antibiotic Range
(mg/L)		 MIC50
(mg/L)		 MIC90
(mg/L)		 % susceptible
at recommended
breakpointa
Haemophilus influenzae
(40)b		 Quinupristin/dalfopristin 1–8 2 2 95
Amoxycillin/clavulanate 0.12–1 0.5 0.5 100
Erythromycin 0.5–4 2 4 NA
Ceftriaxone 0.06 0.06 0.06 100
Ciprofloxacin 0.03–1 0.03 0.03 100
Moraxella catarrhalis
(30)c		 Quinupristin/dalfopristin 0.06–0.25 0.25 0.25 100
Amoxycillin/clavulanate 0.12–0.25 0.12 0.25 100
Erythromycin 0.06–0.5 0.25 0.25 100
Ceftriaxone 0.06–1 0.5 1 100
Ciprofloxacin 0.03–0.06 0.03 0.06 100
  • NA, not applicable.
  • aAccording to NCCLS recommended guidelines [19], Barry et al [37] and Tenover and Baker [38].
  • bIncluding eight β-lactamase-producing strains.
  • cIncluding 13 β-lactamase-producing strains.
Table 7. In vitro activity of quinupristin/dalfopristin and other drugs against 55 anaerobes
Organism
(number tested)		 Antibiotic Range
(mg/L)		 MIC50
(mg/L)		 MIC90
(mg/L)		 % susceptible
at recommended
breakpointa
Gram-positive
(30)b		 Quinupristin/dalfopristin 0.06–2 0.12 0.25 97
Metronidazole 0.06–0.5 0.25 0.25 100
Chloramphenicol 0.25–32 0.5 4 93
Erythromycin 0.5 to >128 0.5 >128 73
Cefoxitin 0.5–128 1 128 67
Clindamycin 0.12 to >128 0.12 >128 77
Vancomycin 0.25–2 0.5 1 100
Gram-negative
(25)c		 Quinupristin/dalfopristin 0.06–4 1 2 72
Metronidazole 0.12–8 0.5 0.5 100
Chloramphenicol 0.5–64 2 4 96
Erythromycin 0.5 to >128 8 >128 24
Cefoxitin 0.5–32 8 32 84
Clindamycin 0.12 to >128 2 >128 52
  • aAccording to NCCLS recommended guidelines [20], Barry et al [37], and Tenover and Baker [38].
  • bClostridium difficile 24, Eubacterium lentum 1, Peptostreptococcus magnus 1, Peptostreptococcus anaerobious 1, Peptostreptococcus asaccharolyticus 1, Peptostreptococcus micros 2.
  • cBacteroides fragilis 13, Bacteroides vulgatus 3, Bacteroides distasonis 3, Bacteroides thetaiotaomicron 6.

Susceptibility tests

The drugs tested varied according to the species considered, as shown in Tables 1–7. They were supplied by the manufacturers: quinupristin/dalfopristin (Rhône-Poulenc Rorer, Milan, Italy); penicillin (Bristol-Myers Squibb, Rome, Italy); ceftriaxone (Roche, Milan, Italy); ciprofloxacin (Bayer, Milan, Italy); erythromycin (Abbott, Campoverde, Italy); vancomycin (Lilly, Sesto Fiorentino, Italy); teicoplanin (Lepetit, Gerenzano, Italy); gentamicin (Schering-Plough, Milan, Italy); amoxycillin—clavulanate (SmithKline Beecham, Milan, Italy); oxacillin, cefoxitin, doxycycline, clindamycin, chloramphenicol and metronidazole (Sigma, Milan, Italy). Sterile stock solutions of the antibiotics were prepared from the standard reference powders in accordance with the instructions received.

Minimum inhibitory concentrations (MICs) of the antimicrobial agents were determined by the agar dilution method following the procedure defined by the National Committee for Clinical Laboratory Standards, using Mueller—Hinton agar (Difco Laboratories, Detroit, MI, USA) as test medium [19]. For tests performed with streptococci, 5% defibrinated lysed horse blood was added to the Mueller—Hinton medium, whereas for evaluation of H. influenzae, Haemophilus Test Medium (HTM) was employed. MICs of anaerobic bacteria were determined by the agar dilution method following the NCCLS procedure [20], using Wilkins—Chalgren agar (Difco Laboratories) as test medium. Plates containing antibiotic and control plates (no antibiotic) were incubated in an anaerobic chamber at 36°C for 48 h. The MIC was defined as the lowest concentration of antibiotic that yielded no visible growth.

The following organisms were included in the assays for quality control: Escherichia coli 25922, Staphylococcus aureus 29213, Enterococcus faecalis 29212, Pseudomonas aeruginosa 27852, Streptococcus pneumoniae 49619, H. influenzae 49247, Bacteroides fragilis 25285 and Bacteroides thetaiotaomicron 229741.

RESULTS

The in vitro susceptibilities of staphylococci to quinupristin/dalfopristin and to other drugs tested are shown in Table 1. Oxacillin-sensitive (oxaS) Staphylococcus aureus strains were all inhibited by quinupristin/dalfopristin at 0.5 mg/L, while the oxacillin-resistant (oxaR) Staphylococcus aureus isolates were inhibited at concentrations of 1 mg/L.

Against coagulase-negative staphylococci (CNS). all drugs showed patterns of activity similar to those with Staphylococcus aureus. Overall, against all staphylococcal species, quinupristin/dalfopristin, teicoplanin and vancomycin qualified as the most potent antibiotics (100% of strains inhibited). Except for erythromycin. Streptococcus pyogenes strains, irrespective of their resistance phenotype, and other β-hemolytic streptococci (Tables 2 and 3) were exquisitely susceptible to all the compounds assayed, with 100% of the strains inhibited and with MIC90 values ranging from <0.06 to 0.25 mg/L. The other streptococci studied, including 18 representatives of Streptococcus sanguis (Table 3), were totally inhibited by quinupristin/dalfopristin and the other compounds assayed.

All Streptococcus pneumoniae strains tested were inhibited by 1 mg/L of quinupristin/dalfopristin irrespective of their resistance to penicillin and/or erythromycin (Table 4). Penicillin-resistant and intermediate isolates were poorly inhibited by erythromycin (20–50% of susceptible strains) and ciprofloxacin (MIC50=2 mg/L). Moreover, only ciprofloxacin (MIC90=2 mg/L) was less potent than the other drugs against erythromycin-resistant pathogens. Table 5 summarizes the results of the susceptibility tests carried out with the enterococci. Vancomycin-susceptible (vanS) Enterococcus faecalis strains were not susceptible to quinupristin/dalfopristin and erythromycin, while teicoplanin and vancomycin, as expected, inhibited all the isolates. The few representatives (five isolates) of vancomycin-resistant (vanR) Enterococcus faecalis were refractory to all the drugs examined. VanS Enterococcus faecium isolates were inhibited by quinupristin/dalfopristin (82%), gentamicin (71%), doxycycline (41%) and ciprofloxacin (12%), while this species was fully susceptible to both teicoplanin and vancomycin. The seven isolates of vanR Enterococcus faecium were poorly susceptible to all antimicrobial agents considered, although quinupristin/dalfopristin showed the lowest MIC range (0.25–8 mg/L).

The data obtained from Gram-negative respiratory pathogens tested are displayed in Table 6. H. influenzae showed high susceptibility to all the antibiotics examined in terms of both MIC90 values and percentage of strains inhibited (100%).

M. catarrhalis remained susceptible to quinupristin/dalfopristin and all other agents, irrespective of β-lactamase production. The concentration of quinupristin/dalfopristin inhibiting 90% of Gram-positive anaerobes was 0.25 mg/L (Table 7), while that for metronidazole and vancomycin was 1 mg/L and that for chloramphenicol was 4 mg/L.

DISCUSSION

The susceptibility of oxacillin-resistant staphylococci to quinupristin/dalfopristin is of special interest, since the proportion of oxacillin-resistant and multiresistant strains exceeds 34% in Italy [21] and appears to be increasing [22]. Staphylococci are the only major pathogens in which the incidence of resistance is directly comparable to the figures reported for other European countries [21]. These microorganisms are particularly difficult to treat, as they are not only insensitive to all β-lactam antibiotics but they are also generally refractory to other classes of drugs such as macrolides, rifampin, tetracycline and fluoroquinolones [1, 4, 23]. Reports suggest that the widespread use of vancomycin is selecting poorly susceptible Staphylococcus aureus in areas where this is the only glycopeptide available, although the stage of full resistance has not yet been reached [6, 7]. The use of quinupristin/dalfopristin may therefore be beneficial in the treatment of infections sustained by oxacillin- and/or vancomycin-resistant staphylococci, should they appear. If widely employed, quinupristin/dalfopristin may diminish the strong selective pressure presently exerted by the glycopeptides.

The same assumption may hold true for multiresistant enterococci, which while a common cause of nosocomial infections, at present rarely display glycopeptide resistance in Italy [24]. Glycopeptide resistance is known to accumulate preferentially in Enterococcus faecium. The role of quinupristin/dalfopristin seems, therefore, even more attractive, since this is the clinically important species on which the new drug exerts a useful activity, a fact also anticipated in the literature [13, 25].

Streptococcus pyogenes remains fully susceptible to penicillins and other β-lactams [26]. However, its sensitivity to macrolides has been known to vary and has increased in certain regions [8]. In Italy, various recent surveys have placed overall resistance to erythromycin in Streptococcus pyogenes at around 40% [27–29]. This present increased incidence of macrolide resistance in our country resembles a similar episode described several years ago in Japan [30], although a mechanistic explanation for its occurrence has yet to be demonstrated. In particular, about 40% of the erythromycin-resistant strains now circulating show the high-level constitutive phenotype that diminishes the efficacy of 14-, 15-, and 16-membered macrolides, lncosamides and streptogramin B [8]. Quinupristin/dalfopristiu, which has been found to overcome not only inducible (I) and M-type but also constitutive macrolide resistance, might be employed in serious infections caused by Streptococcus pyogenes in areas such as Italy, where this trait has become widespread.

Multiresistance in Streptococcus pneumoniae is a universal problem [10]. This microorganism is responsible for several important infections and remains a leading cause of morbidity and mortality worldwide despite the availability of several antimicrobial agents that perform adequately in vitro [31]. Although, for non-meningitic infections, high-dose penicillin remains clinically effective [32], this type of treatment is risky and may not always be successful [33, 34]. If penicillin resistance increases to levels exceeding 4 mg/L in routine isolates of this pathogen, therapy with other drugs will become necessary [35]. In Italy, the incidence of penicillin-resistant Streptococcus pneumoniae has remained relatively low (14.3%), in this country, 50% of these organisms display insensitivity to the available injectable third-generation cephalosporins [18]. Given the possibility of further spreading driven by the high consumption of these drugs in our country [16], therapy of the more severe infections (meningitis, septicemia) might eventually become exceedingly difficult. Considering the exquisite susceptibility of these isolates to quinupristin/dalfopristin, as well as the penetration of this molecule in cerebrospinal fluid [36] of animal models, the new injectable streptogramin may represent a good therapeutic option in difficult-to-treat conditions if these findings are confirmed in humans.

The fact that Gram-negative pathogens such as H. influenzae and M. catarrhalis and most Gram-positive anaerobes are easily inhibited by quinupristin/dalfopristin extends the usefulness of the new drug, which may thus encompass respiratory and mixed infections.

Taken together, these findings suggest a role for quinupristin/dalfopristin in the empirical treatment of a broad range of nosocomial and community-acquired infections deemed to be sustained by pathogens often characterized by multiple antimicrobial resistance.

Acknowledgments

A preliminary account of this work was presented at the 8th European Congress of Clinical Microbiology and Infectious Diseases, Lausanne, Switzerland, 1997.

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