quinupristin-dalfopristin and Endocarditis--Bacterial

Gram-positive cocci, mainly streptococci and staphylococci, continue to cause the majority of cases of infective endocarditis. Among the streptococci causing IE, the long-standing predominance of oral or viridans-group streptococci has progressively faded, while the number of cases caused by "enteric streptococci" (Streptococcus bovis and enterococci) has increased. While most oral streptococci and S. bovis strains remain fully sensitive to penicillin, nutritionally variant streptococci--now renamed Abiotrophia--and enterococci can exhibit resistance to penicillin and/or glycopeptides that makes endocarditis more difficult to treat. Among the staphylococci causing endocarditis, the increasing proportion of coagulase-negative and methicillin-resistant strains observed in recent years has changed the approach to choice of antibiotic therapy. The purpose of this paper is to focus on some new aspects of the management of antibiotic therapy of IE due to streptococci and staphylococci, including recent developments such as once-daily aminoglycoside administration in IE, outpatient antibiotic therapy, and the evaluation of new antibiotics.

Topics: Acetamides; Aminoglycosides; Animals; Anti-Bacterial Agents; Disease Management; Drug Resistance; Endocarditis, Bacterial; Enterococcus; Gram-Positive Cocci; Humans; Linezolid; Oxazolidinones; Staphylococcus aureus; Streptococcus; Streptococcus pneumoniae; Virginiamycin

INJECTABLE SPECTROGRAMIN: Combination regimens using quinupristin/dafopristin with either gentamicin or vancomycin have powerful bactericidal activities (even against quinupristin-resistant strains) against methicillin-resistant Staphylococcus aureus (MRSA) in a model of experimental endocarditis in the rabbit. In clinical trials, quinupristin/dalfopristin is becoming a therapeutic alternative to consider after failure of conventional antistaphylococcal treatments. NEW GENERATION CEPHALOSPORINS: These new cephalosporins, particularly C-3 pyridinium-thiomethyl-cephalosporins, new (3-dithiocarbamoyl) cephalosporins, and a series of new compounds with high affinity for MRSA PLP2a, are particularly active against MRSA and are unaffected by beta-lactamases. A NEW CARBAPENEM: This new antibiotic has a wide bactericidal effect against Gram-positive organisms and is active against MRSA as well as penicillin-resistant S. pneumoniae. NEW FLUOROQUINOLONE DERIVATIVES: In vitro, these new derivatives have been found to be active against MRSA, pneumococci non-sensitive to ciprofloxacin, and Bacteroides fragilis, Mycobacterium tuberculosis, Chlamydia pneumoniae.

Topics: Anti-Infective Agents; Carbapenems; Cephalosporins; Drug Therapy, Combination; Endocarditis, Bacterial; Fluoroquinolones; Humans; Methicillin Resistance; Staphylococcal Infections; Virginiamycin

Quinupristin/dalfopristin is a semisynthetic parenteral streptogramin combination consisting of two components, quinupristin (RP 57669) and dalfopristin (RP 54476), in a 30:70 (w/w) ratio. These compounds act synergically against many Gram-positive bacteria that cause severe infections. Several animal models have been used to study the in-vivo efficacy and pharmacodynamics of quinupristin/dalfopristin against infections caused by Staphylococcus aureus and Streptococcus spp. Studies of its efficacy in animal models of septicaemia, thigh infection, pneumonia and aortic endocarditis have shown it to be as active as vancomycin against S. aureus, including some methicillin-resistant strains (MRSA), and as active as high doses of amoxycillin against penicillin-resistant and multi-resistant strains of Streptococcus pneumoniae. Thus, quinupristin/dalforpristin appears to have potential as an alternative to vancomycin in the management of severe staphylococcal and streptococcal infections, including those caused by MRSA and multi-resistant pneumococci.

Topics: Animals; Anti-Bacterial Agents; Chinchilla; Disease Models, Animal; Endocarditis, Bacterial; Lung Diseases; Mice; Rats; Sepsis; Virginiamycin

We used an experimental rat model to compare the therapeutic efficacy of teicoplanin, linezolid, and quinupristin/dalfopristin with that of vancomycin as standard therapy for infective endocarditis.Aortic endocarditis was induced in rats by insertion of a polyethylene catheter into the left ventricle, followed by intravenous inoculation of 106 colony-forming units of methicillin-resistant Staphylococcus aureus 24 hours later. Forty-eight hours after bacterial challenge, intravenous antibiotic therapies were initiated. There were 6 groups of 8 rats each: uninfected control; infected, untreated control; vancomycin-treated (40 mg/kg twice daily); teicoplanin-treated (20 mg/kg twice daily after a loading dose of 40 mg/kg); linezolid-treated (75 mg/kg 3 times daily for 1 day, then 75 mg/kg twice daily); and quinupristin/dalfopristin-treated (30 mg/kg twice daily and an additional 10 mg/kg dalfopristin infusion over 6 to 12 hr daily). At the end of therapy, the aortic valve vegetations in the drug-treated rats were evaluated microbiologically.Compared with the infected, untreated group, all drug-treated groups had significantly reduced bacterial titers in the vegetations. Vancomycin, teicoplanin, and quinupristin/dalfopristin all effectively reduced the quantitative bacterial cultures of aortic valve vegetations. In addition, there was no significant difference in the comparative efficacy of teicoplanin, linezolid, and quinupristin/dalfopristin. Vancomycin significantly reduced bacterial counts in comparison with linezolid, which was nonetheless also effective.Our experimental model showed that each of the investigated antimicrobial agents was effective in the treatment of infective endocarditis.

Topics: Acetamides; Animals; Anti-Infective Agents; Aortic Valve; Colony Count, Microbial; Disease Models, Animal; Endocarditis, Bacterial; Infusions, Intravenous; Injections, Intravenous; Linezolid; Male; Methicillin-Resistant Staphylococcus aureus; Oxazolidinones; Rats; Rats, Wistar; Teicoplanin; Time Factors; Vancomycin; Virginiamycin

Following an initial response to vancomycin therapy, a patient with meticillin-resistant Staphylococcus aureus (MRSA) bacteraemia developed endocarditis, failed a second course of vancomycin and then failed daptomycin therapy. An increase in the vancomycin minimum inhibitory concentrations of four consecutive MRSA blood isolates from 2 microg/mL to 8 microg/mL was shown by Etest. Population analysis of four successive blood culture isolates recovered over the 10-week period showed that the MRSA strain became progressively less susceptible to both vancomycin and daptomycin. Retrospectively, the macro Etest method using teicoplanin indicated a decrease in vancomycin susceptibility in the second blood isolate. The patient improved after treatment with various courses of trimethoprim/sulfamethoxazole, quinupristin/dalfopristin and linezolid. Early detection of vancomycin-heteroresistant S. aureus isolates, which appeared to have clinical significance in this case, continues to be a challenge for the clinical laboratory. Development of suitable practical methods for this should be given priority. Concurrent development of resistance to vancomycin and daptomycin, whilst rare, must be considered in a patient who is unresponsive to daptomycin following vancomycin therapy.

Topics: Acetamides; Anti-Bacterial Agents; Bacteremia; Daptomycin; Drug Resistance, Bacterial; Endocarditis, Bacterial; Humans; Linezolid; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Oxazolidinones; Staphylococcal Infections; Trimethoprim, Sulfamethoxazole Drug Combination; Vancomycin; Virginiamycin

Methicillin-resistant S. aureus (MRSA) with low susceptibility to glycopeptides is uncommon.. The case of a 50-year-old non-drug addict patient presenting with tricuspid valve infective endocarditis (IE) by MRSA resistant to vancomycin and linezolid is presented. There was response only to quinupristin/dalfopristin. He had a motorcycling accident four years before undergoing right above-the-knee amputation and orthopaedic fixation of the left limb. There were multiple episodes of left MRSA-osteomyelitis controlled after surgery and vancomycin therapy. MRSA isolated from the blood at the time of IE presented with the same profile than the isolated four years earlier. Sequential treatment with teicoplanin-cotrimoxazole and Linezolid associated to vancomycin--rifampicin--cotrimoxazole had no improvement. Infection was controlled after 28 days of therapy with quinupristin/dalfopristin.. The literature presents only a few cases of MRSA IE not susceptible to glycopeptides in not drug addicted patients. This case shows the comparison of a highly-resistant MRSA after previous S. aureus osteomyelitis treated with glycopeptides. This is the first description of successful treatment of resistant-MRSA IE of the tricuspid valve complicated by multiple pulmonary septic infarction with quinupristin/dalfopristin.

Topics: Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Endocarditis, Bacterial; Heart Valve Diseases; Humans; Male; Methicillin Resistance; Middle Aged; Osteomyelitis; Radiography; Staphylococcal Infections; Staphylococcus aureus; Substance-Related Disorders; Tricuspid Valve; Ultrasonography; Virginiamycin

The incidence of multidrug-resistant Enterococcus faecium is increasing despite advances in antibacterial therapy. Thus, new antibiotics are required to treat hospital- or community-acquired infections caused by these multidrug-resistant organisms. The aim of this study was to compare the therapeutic efficacy of quinupristin-dalfopristin (QD) alone, or in combination with gentamicin (G), teicoplanin (T), imipenem (I) or levofloxacin (L) against a strain of multidrug-resistant E. faecium in an experimental model of aortic valve endocarditis in rabbits. The study group consisted of 28 control animals. Eighty-two animals were treated with one of the following antibiotic regimens: G1: 18 animals QD (30 mg/kg/8 h); G2: 18 animals QD+G (6 mg/kg/12 h); G3: 16 animals QD+T (20 mg/kg/12 h); G4: 14 animals QD+I (60 mg/kg/8 h); and G5: 16 animals QD+L (20 mg/kg/12 h). The response to therapy was determined by the comparison of the number of CFU/g of E. faecium in each vegetation. In vitro, time-kill studies looking for synergy for the combinations that showed better efficacy in vivo were done. The sensitivity of the strain was intermediate to QD, resistant to T and I, and sensitive to L. There was no high-level resistance to G. QD alone revealed a significant decrease (p <0.001) in the CFU/g in the control group (9.49 vs. 7.31). There were no differences in the average of CFU/g between the QD alone (G1), QD+G (G2) and QD+T (G3) groups. These three groups revealed a significant difference in decrease of CFU/g respect of the group control (p <0.001). There were no differences in the average of CFU/g between QD+I (G4) and QD+T (G5). These two groups revealed the greatest decrease in average CFU/g (G4: 4.38 and G5: 4.04) with differences respect of the group control (p <0.0001) and respect of the groups G1, G2 and G3 (p <0.001). We did not detect any alteration of MIC from QD in the course of the treatment for either of the final isolations. Only the time kill corresponding to concentrations of I 32 mg/l (0.25 x MIC) and QD 1 mg/l (0.25 x MIC presents a descending slope in the curve at 4 and 8 h, suggesting an early synergy phenomenon, which was lost after 8 h. In light of these results, the combination QD with I and L may be considered suitable alternatives for the treatment of multiresistant E. faecium.

Topics: Aged; Animals; Anti-Bacterial Agents; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Endocarditis, Bacterial; Enterococcus faecium; Female; Gentamicins; Gram-Positive Bacterial Infections; Humans; Imipenem; Levofloxacin; Microbial Sensitivity Tests; Ofloxacin; Rabbits; Teicoplanin; Virginiamycin

A beneficial effect of the combination of quinupristin-dalfopristin and vancomycin was observed against two methicillin-resistant strains of Staphylococcus aureus harboring or not harboring the ermC gene, which codes for constitutive macrolide, lincosamide, and streptogramin B resistance. The beneficial effect was observed in time-kill studies, in which the drugs were used at inhibitory concentrations, and in a rabbit model of endocarditis, in which the combination was highly bactericidal and more active than monotherapies.

Topics: Animals; Anti-Bacterial Agents; Culture Media; Drug Resistance; Drug Therapy, Combination; Endocarditis, Bacterial; Lincosamides; Macrolides; Methicillin Resistance; Microbial Sensitivity Tests; Rabbits; Staphylococcus aureus; Streptogramin B; Time Factors; Vancomycin; Virginiamycin

We describe a patient with early post-surgical infective endocarditis due to methicillin-resistant Staphylococcus aureus, who was unsuitable for surgical reintervention and who failed standard antistaphylococcal therapy, but was successfully cured with a sequential regimen including quinupristin/dalfopristin and linezolid.

Topics: Acetamides; Aged; Aged, 80 and over; Anti-Infective Agents; Cardiovascular Surgical Procedures; Drug Administration Schedule; Drug Therapy, Combination; Endocarditis, Bacterial; Female; Humans; Linezolid; Methicillin Resistance; Mitral Valve Insufficiency; Oxazolidinones; Staphylococcal Infections; Surgical Wound Infection; Virginiamycin

The combination of quinupristin-dalfopristin (Q-D) and gentamicin was tested against two strains of gentamicin- and dalfopristin-susceptible methicillin-resistant Staphylococcus aureus (MRSA). One strain was susceptible to macrolides, lincosamides, and streptogramin B type antibiotics (MLS(B)), and the other was constitutively resistant to these antibiotics by virtue of the ermA gene. The checkerboard method and time-kill curves showed that the combination of Q-D and gentamicin was indifferent. A rabbit endocarditis model simulated the pharmacokinetics achieved in humans receiving intravenous injections of Q-D (7.5 mg/kg of body weight three times a day) and gentamicin (3 mg/kg once daily). For the MLS(B)-susceptible strain, a 4-day regimen reduced mean bacterial titers (MBT) in vegetations from 8.5 +/- 0.8 log CFU/g (control group) to 4.1 +/- 2.6 (gentamicin), 3.0 +/- 0.9 (Q-D), and 2.6 +/- 0.5 log CFU/g (Q-D plus gentamicin). For the strain constitutively resistant to MLS(B), a 4-day regimen reduced MBT in vegetations from 8.7 +/- 0.9 log CFU/g (control group) to 5.0 +/- 2.2 (gentamicin), 5.2 +/- 2.2 (Q-D), and 5.1 +/- 2.4 log CFU/g (Q-D plus gentamicin). The differences between control and treatment groups were significant for both strains (P < 0.0001), although there was no significant difference between treatment groups. No resistant variant was isolated from vegetations, and no significant difference in MBT in vegetations of treatment groups after 1-day regimens was observed. This experimental study found no additive benefit in combining Q-D and gentamicin against dalfopristin- and gentamicin-susceptible MRSA.

Topics: Animals; Drug Therapy, Combination; Endocarditis, Bacterial; Gentamicins; Methicillin Resistance; Microbial Sensitivity Tests; Rabbits; Staphylococcal Infections; Virginiamycin

We evaluated the activities of quinupristin-dalfopristin (Q-D), alone or in combination with rifampin, against three strains of Staphylococcus aureus susceptible to rifampin (MIC, 0.06 microg/ml) and to Q-D (MICs, 0.5 to 1 microg/ml) but displaying various phenotypes of resistance to macrolide-lincosamide-streptogramin antibiotics: S. aureus HM1054 was susceptible to quinupristin and dalfopristin (MICs of 8 and 4 microg/ml, respectively); for S. aureus RP13, the MIC of dalfopristin was high (MICs of quinupristin and dalfopristin for strain RP13, 8 and 32 microg/ml, respectively); and S. aureus HM1054R was obtained after conjugative transfer of macrolide-lincosamide-streptogramin B constitutive resistance to HM1054, and the MIC of quinupristin for this strain was high (MICs of quinupristin and dalfopristin, 64 and 4 microg/ml, respectively). In vitro time-kill curve studies showed an additive effect [corrected] between Q-D and rifampin, at a concentration of four times the MIC, against the three strains. Rabbits with aortic endocarditis were treated 4 days with Q-D, rifampin, or their combination. In vivo, the combination was highly bactericidal and synergistic against strains susceptible to quinupristin (HM1054 and RP13) and sterilized 94% of the animals. In contrast, the combination was neither synergistic nor bactericidal against the quinupristin-resistant strain (HM1054R) and did not prevent the emergence of mutants resistant to rifampin. We conclude that the in vivo synergistic and bactericidal activity of the combination of Q-D and rifampin against S. aureus is predicted by the absence of resistance to quinupristin but not by in vitro combination studies.

Topics: Animals; Anti-Bacterial Agents; Drug Resistance, Microbial; Drug Synergism; Drug Therapy, Combination; Endocarditis, Bacterial; Female; Kinetics; Lincosamides; Macrolides; Microbial Sensitivity Tests; Mutation; Phenotype; Rabbits; Rifampin; Staphylococcal Infections; Staphylococcus aureus; 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

SYNERCID ALONE IN A RAT MODEL OF EXPERIMENTAL ENDOCARDITIS: Trials conducted using 2 injections daily showed that animals infected with meti-R resistant Staphylococcus aureus strains sensitive to erythromycin were cured in 3 days. The same is not true for infections caused by C-MLSB-R staphylococci. The daily dose cannot be increased due to the venous toxicity of Synercid, leading to the idea of testing Synercid in combination with other antibiotics.. Several antibiotics have been tested in combination with Synercid. Several beta-lactams have been shown to exhibit an additive or synergetic effect on a collection of meti-R and meti-S S. aureus strains.. In animals infected with C-MLSB-R meti-R S. aureus, the combination Synercid + cefepime increases the activity of cefipime and prevents selection of beta-lactam highly resistant strains. The results obtained with the Synercid + cefpirome combination are even more eloquent. Finally, Synercid, alone or in combination with these 2 cephalosporins, does not select resistant strains.

Topics: Animals; Anti-Bacterial Agents; beta-Lactams; Drug Synergism; Drug Therapy, Combination; Endocarditis, Bacterial; Humans; Rats; Staphylococcal Infections; Virginiamycin

Quinupristin-dalfopristin (Q-D) is an injectable streptogramin active against most gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). In experimental endocarditis, however, Q-D was less efficacious against MRSA isolates constitutively resistant to macrolide-lincosamide-streptogram B (C-MLS(B)) than against MLS(B)-susceptible isolates. To circumvent this problem, we used the checkerboard method to screen drug combinations that would increase the efficacy of Q-D against such bacteria. beta-Lactams consistently exhibited additive or synergistic activity with Q-D. Glycopeptides, quinolones, and aminoglycosides were indifferent. No drugs were antagonistic. The positive Q-D-beta-lactam interaction was independent of MLS(B) or beta-lactam resistance. Moreover, addition of Q-D at one-fourth the MIC to flucloxacillin-containing plates decreased the flucloxacillin MIC for MRSA from 500 to 1,000 mg/liter to 30 to 60 mg/liter. Yet, Q-D-beta-lactam combinations were not synergistic in bactericidal tests. Rats with aortic vegetations were infected with two C-MLS(B)-resistant MRSA isolates (isolates AW7 and P8) and were treated for 3 or 5 days with drug dosages simulating the following treatments in humans: (i) Q-D at 7 mg/kg two times a day (b.i.d.) (a relatively low dosage purposely used to help detect positive drug interactions), (ii) cefamandole at constant levels in serum of 30 mg/liter, (iii) cefepime at 2 g b.i.d., (iv) Q-D combined with either cefamandole or cefepime. Any of the drugs used alone resulted in treatment failure. In contrast, Q-D plus either cefamandole or cefepime significantly decreased valve infection compared to the levels of infection for both untreated controls and those that received monotherapy (P < 0.05). Importantly, Q-D prevented the growth of highly beta-lactam-resistant MRSA in vivo. The mechanism of this beneficial drug interaction is unknown. However, Q-D-beta-lactam combinations might be useful for the treatment of complicated infections caused by multiple organisms, including MRSA.

Topics: Animals; Anti-Bacterial Agents; Cefamandole; Cefepime; Cephalosporins; Disease Models, Animal; Drug Resistance, Microbial; Drug Resistance, Multiple; Drug Therapy, Combination; Endocarditis, Bacterial; Humans; Lincosamides; Macrolides; Microbial Sensitivity Tests; Rats; Staphylococcal Infections; Staphylococcus aureus; Time Factors; Virginiamycin

Topics: Adult; Anti-Bacterial Agents; Endocarditis, Bacterial; Humans; Male; Methicillin Resistance; Staphylococcal Infections; Staphylococcus epidermidis; Vancomycin; Virginiamycin

Topics: Aged; Doxycycline; Drug Resistance, Microbial; Drug Synergism; Drug Therapy, Combination; Endocarditis, Bacterial; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Male; Rifampin; Vancomycin; Virginiamycin

The influence of inducible cross-resistance to macrolides, lincosamides, and streptogramin B (MLS(B)) type antibiotics (inducible MLS(B) phenotype) on the activity of quinupristin-dalfopristin was investigated against Enterococcus faecium in vitro and in rabbits with experimental endocarditis. In vitro, quinupristin-dalfopristin displayed bacteriostatic and bactericidal activities against a MLS(B)-susceptible strain similar to those against two strains with the inducible MLS(B) phenotype. In addition, induction of the two MLS(B)-resistant strains with quinupristin (0.016 to 1 microg/ml) or quinupristin-dalfopristin (0.08 to 0.25 microg/ml) increased the MICs of quinupristin from 8 microg/ml to 32 to > 128 microg/ml, but did not modify the MIC of dalfopristin (2 microg/ml) or quinupristin-dalfopristin (0.5 microg/ml). In a rabbit endocarditis model, quinupristin-dalfopristin was as active as amoxicillin against the MLS(B)-susceptible E. faecium strain. In contrast, the activity of quinupristin-dalfopristin was significantly decreased in animals infected with either of the two inducible MLS(B)-resistant strains (P < 0.05), although no mutants resistant to quinupristin-dalfopristin were detected. Against the clinical strain with the inducible MLS(B) phenotype, quinupristin-dalfopristin was not effective and was less active than amoxicillin (P < 0.001); however, the activity of the combination of amoxicillin and dalfopristin-quinupristin was superior to that of amoxicillin (P < 0.01). The different impact of the inducible MLS(B) phenotype in E. faecium on the activity of quinupristin-dalfopristin in vitro and in experimental endocarditis may be related to the reduced diffusion of dalfopristin compared with that of quinupristin into cardiac vegetations that we previously reported. This result emphasizes the importance of the constant presence of dalfopristin at the site of infection to ensure synergism with quinupristin.

Topics: Animals; Anti-Bacterial Agents; Drug Resistance, Microbial; Drug Synergism; Endocarditis, Bacterial; Enterococcus faecium; Female; Lincosamides; Macrolides; Microbial Sensitivity Tests; Rabbits; Virginiamycin

Topics: Anti-Bacterial Agents; Drug Resistance, Microbial; Endocarditis, Bacterial; Enterococcus faecium; Female; Gram-Positive Bacterial Infections; Humans; Middle Aged; Prosthesis-Related Infections; Vancomycin; Virginiamycin

The activity of quinupristin/dalfopristin was compared with that of other widely used antibiotics against 355 strains isolated from patients with endocarditis. MICs were determined by a standard agar dilution method. Quinupristin/dalfopristin was inhibitory at 1 mg/L for all coagulase-negative staphylococci (n = 36) and for the majority of Staphylococcus aureus strains (n = 87). The activity of quinupristin/dalfopristin against 186 viridans streptococci was somewhat dependent on the species, with MIC50s ranging from 0.5 to 2 mg/L, being least active against Streptococcus bovis and most active against Streptococcus gordonii and Streptococcus mitis. For the staphylococci, quinupristin/dalfopristin was as active against erythromycin-susceptible as erythromycin-resistant strains. Viridans streptococci showed a slight but significant correlation between sensitivity to erythromycin and quinupristin/dalfopristin. It is concluded that quinupristin/dalfopristin has the potential to treat serious infections such as endocarditis caused by Gram-positive cocci.

Topics: Anti-Bacterial Agents; Endocarditis, Bacterial; Gram-Positive Bacteria; Humans; Microbial Sensitivity Tests; Streptococcus; Virginiamycin

In-vitro and in-vivo efficacies of quinupristin/dalfopristin and vancomycin against methicillin-resistant Staphylococcus aureus (MRSA) responsible for endocarditis have been compared. The following parameters were investigated: MIC, activity across a platelet-fibrin matrix simulating cardiac vegetations, killing of bacteria on the cardiac vegetations resulting from experimental aortic valve endocarditis in an animal model, and concentrations of antibiotics in the serum and vegetations of infected rabbits. The same bacterial strain was used for all experiments. The MICs of quinupristin/dalfopristin and vancomycin were 0.25 and 1 mg/L, respectively. When tested for their ability to penetrate platelet-fibrin matrices, both drugs were bactericidal against the MRSA strain (> or = 2 log10 cfu/mL decrease in 2 h). Both drugs significantly reduced the bacterial counts in vegetations in infected rabbits. Within 12 h of intravenous administration of 20 mg/kg, concentrations of quinupristin/dalfopristin decreased from 5.3 to < 0.10 mg/L in serum and from 12.9 to < 1 mg/kg in the valve vegetations. Although the concentrations of vancomycin in the serum and the infected tissue were higher than those of quinupristin/dalfopristin, the latter combination was equally effective, perhaps because its bactericidal activity is rapid and because it can more easily penetrate the cardiac vegetations.

Topics: Animals; Anti-Bacterial Agents; Blood Platelets; Colony Count, Microbial; Endocarditis, Bacterial; Male; Methicillin Resistance; Microbial Sensitivity Tests; Rabbits; Staphylococcus aureus; Vancomycin; Virginiamycin

RP 59500 is a new injectable streptogramin composed of two synergistic components (quinupristin and dalfopristin) which are active against erythromycin-susceptible and -resistant gram-positive pathogens. The present experiments compared the therapeutic efficacy of RP 59500 with that of vancomycin against experimental endocarditis due to either of two erythromycin-susceptible or two constitutively erythromycin-resistant isolates of methicillin-resistant Staphylococcus aureus. RP 59500 had low MICs for the four test organisms as well as for 24 additional isolates (the MIC at which 90% of the isolates were inhibited was < 1 mg/liter) which were mostly inducibly (47%) or constitutively (39%) erythromycin resistant. Aortic endocarditis in rats was produced with catheter-induced vegetations. Three-day therapy was initiated 12 h after infection, and the drugs were delivered via a computerized pump, which permitted the mimicking of the drug kinetics produced in human serum by twice-daily intravenous injections of 7 mg of RP 59500 per kg of body weight or 1 g of vancomycin. Both antibiotics reduced vegetation bacterial titers to below detection levels in ca. 70% of animals infected with the erythromycin-susceptible isolates (P < 0.05 compared with titers in controls). Vancomycin was also effective against the constitutively resistant strains, but RP 59500 failed against these isolates. Further experiments proved that RP 59500 failures were related to the very short life span of dalfopristin in serum (< or = 2 h, compared with > or = 6 h for quinupristin), since successful treatment was restored by artificially prolonging the dalfopristin levels for 6 h. Thus, RP 59500 is a promising alternative to vancomycin against methicillin-resistant S. aureus infections, provided that pharmacokinetic parameters are adjusted to afford prolonged levels of both of its constituents in serum. This observation is also relevant to humans, in whom the life span of dalfopristin in serum is also shorter than that of quinupristin.

Topics: Animals; Drug Resistance, Microbial; Endocarditis, Bacterial; Erythromycin; Female; Methicillin Resistance; Microbial Sensitivity Tests; Rats; Rats, Wistar; Staphylococcal Infections; Staphylococcus aureus; Vancomycin; Virginiamycin

RP 59500 is a new injectable streptogramin composed of two synergistic components (quinupristin and dalfopristin) which are active against a number of erythromycin-susceptible and -resistant gram-positive bacteria. The following experiments investigate the ability of RP 59500 to prevent experimental endocarditis due to either of two erythromycin-susceptible streptococcal isolates or their constitutively erythromycin-resistant Tn916 delta E transconjugants. RP 59500 had low MICs (0.125 to 0.5 mg/liter) for all four test organisms and was substantially bactericidal in vitro. Rats with catheter-induced aortic vegetations were given single-dose antibiotic prophylaxis 30 to 60 min before bacterial inoculation through a computerized pump system which permitted the simulation of drug kinetics for humans produced by either 7 mg of RP 59500 per kg of body weight or 1 g of vancomycin. Single-dose RP 59500 prophylaxis successfully prevented endocarditis due to both the erythromycin-susceptible parent strains and their erythromycin-resistant derivatives in rats challenged with the minimal inoculum infecting 90% of controls. In addition, RP 59500 also prevented infection in animals challenged with fivefold-larger inocula of the erythromycin-susceptible parent strains. Vancomycin successfully prevented endocarditis due to any of the four test organisms. These results underline the in vivo efficacy of RP 59500 against both erythromycin-susceptible and -resistant streptococci. Such good results against the resistant strains would not be expected with erythromycin or clindamycin, which are the standard macrolidelincosamide-streptogramin antibiotics used for endocarditis prophylaxis in humans. An oral form of RP 59500 which might advantageously replace some of the older prophylactic regimens is currently being developed.

Topics: Animals; Conjugation, Genetic; Drug Resistance, Microbial; Endocarditis, Bacterial; Erythromycin; Female; Microbial Sensitivity Tests; Rats; Rats, Wistar; Streptococcal Infections; Streptococcus; Vancomycin; Virginiamycin

In order to determine the microbiological and pharmacokinetic parameters that best predicted the in vivo antistaphylococcal activity of the streptogramin RP 59500 (quinupristin-dalfopristin), we evaluated the activity in rabbit aortic endocarditis of three regimens of quinupristin-dalfopristin against five strains of Staphylococcus aureus with various streptogramin B-type antibiotic resistance phenotypes and susceptible to streptogramin A-type antibiotics. Quinupristin-dalfopristin was as active as vancomycin against three strains that were susceptible to its streptogramin B component quinupristin, including one strain that was inducibly resistant to erythromycin, but had a significantly decreased activity against two strains that were resistant to quinupristin, for all quinupristin-dalfopristin regimens tested (P < 0.05). The area under the concentration-time curve for quinupristin-dalfopristin in plasma divided by the MIC of quinupristin was the only parameter retained by multilinear regression that predicted the in vivo activity of quinupristin-dalfopristin (P = 0.0001), emphasizing the importance of determining the susceptibility to quinupristin in order to predict the in vivo activity of quinupristin-dalfopristin against S. aureus.

Topics: Animals; Drug Resistance, Microbial; Endocarditis, Bacterial; Female; Rabbits; Staphylococcal Infections; Staphylococcus aureus; Vancomycin; Virginiamycin

We evaluated the in vivo activity and the diffusion of radiolabelled RP 57669 (RPI) and RP 54476 (RPII), the two components of the injectable streptogramin RP 59500, alone or in combination, in aortic vegetations from experimental endocarditis in rabbits. RPI and RPII demonstrated in vitro bacteriostatic and bactericidal synergy against a clinical strain of Staphylococcus aureus resistant to methicillin and susceptible to erythromycin. In experimental staphylococcal endocarditis, RP 59500 was as effective as vancomycin and significantly more effective than RPI (P < 0.01) and RPII (P < 0.05). Autoradiography studies showed different patterns of distribution into cardiac vegetations infected with Streptococcus sanguis for [14C]RPI and [14C]RPII. [14C]RPI was homogeneously distributed throughout the vegetations whereas [14C]RPII showed a decreasing gradient of concentration between the periphery and the core of the vegetation, with an approximately 2:1 ratio. [14C]RPI diffused approximately 2 to 4 times more than [14C]RPII into the core of the vegetations. Since the injected ratio of RPI and RPII is 30:70 in RP 59500, the actual RPI:RPII ratio in the core of the vegetation may range from 0.8 to 1.7, a ratio which remains compatible with the in vivo synergism demonstrated between the two components.

Topics: Animals; Autoradiography; Culture Media; Drug Synergism; Endocarditis, Bacterial; Female; Humans; Methicillin Resistance; Microbial Sensitivity Tests; Rabbits; Staphylococcal Infections; Staphylococcus aureus; Streptococcal Infections; Streptococcus sanguis; Vancomycin; Virginiamycin

The activity of RP 59500 against methicillin-resistant Staphylococcus aureus was studied in vitro and in a rabbit model of aortic valve endocarditis. Three strains, 67-O, 529, and Du, ranging from relatively resistant to susceptible to RP 59500 in vitro (mean agar dilution MICs of 0.65, 0.21, and 0.12 mg/L respectively) were used to establish endocarditis, which was treated either with RP 59500, 20 mg/kg im four times a day for four days or with vancomycin, 25 mg/kg iv twice a day for four days. RP 59500 was ineffective for the most resistant strain, 67-O. RP 59500 was effective for the intermediately susceptible strain 529, but vancomycin was more effective. RP 59500 was slightly more effective than vancomycin against the most susceptible strain, Du, but the difference was not statistically significant. These results suggest that strains inhibited by RP 59500 at a concentration of greater than or equal to 0.5 mg/L should probably be considered resistant in this model of infection. RP 59500 was effective in vivo against the two susceptible strains, but overall, vancomycin was the more active drug.

Topics: Animals; Aortic Valve; Drug Combinations; Drug Resistance, Microbial; Endocarditis, Bacterial; Heart Valve Diseases; In Vitro Techniques; Methicillin; Microbial Sensitivity Tests; Rabbits; Staphylococcal Infections; Staphylococcus aureus; Vancomycin; Virginiamycin