Evaluation of fusidic acid in therapy of experimental Staphylococcus aureus meningitis

OBJECTIVES: Combination therapy that includes fusidic acid, an antimicrobial agent highly active against staphylococci, has been recommended in the treatment of patients with Staphylococcus aureus meningitis. The aim of this study was to evaluate the pharmacokinetic, CSF bactericidal and anti-inflammatory properties of fusidic acid. METHODS: The pharmacokinetics, treatment efficacy and parameters of the meningeal inflammatory response were studied in rabbits, using an experimental meningitis model against S. aureus (MICs of fusidic acid and methicillin were 0.125 and 1 mg/L, respectively). RESULTS: Fusidic acid entered the CSF, with peak values within 0.5-1 h of the intravenous bolus injection/infusion and with a percentage penetration (AUCCSF/AUCserum) into uninfected and purulent CSF of 1.9% +/- 0.7 and 4.5% +/- 0.7, respectively. Rabbits treated with antibiotics [fusidic acid 80 mg/kg/6 h (n = 6), methicillin 80 mg/kg/3 h (n = 7) and the two combined (n = 6)] had significantly higher bacterial kill rates than untreated controls (n = 6, P < 0.05). Combination therapy was less effective, with significantly less killing after 6 h of treatment than methicillin alone (P < 0.05). CSF white blood cells and CSF levels of interleukin-8 (IL-8), glucose, lactate and protein were altered during staphylococcal meningitis, but with no significant difference between antibiotic-treated and untreated rabbits. CONCLUSIONS: Antagonism between methicillin and fusidic acid was observed in staphylococcal meningitis.     

Teicoplanin versus nafcillin and vancomycin in the treatment of experimental endocarditis caused by methicillin-susceptible or -resistant Staphylococcus aureus.

In rabbits with experimentally induced endocarditis, the efficacy of teicoplanin compared favorably both with that of nafcillin for infection by a methicillin-susceptible strain of Staphylococcus aureus and with that of vancomycin for infection by a methicillin-resistant strain of S. aureus. In a 4-day treatment regimen, teicoplanin was as effective as either nafcillin or vancomycin in eliminating organisms from aortic valve vegetations in the respective infection. In a 10-day regimen for methicillin-resistant S. aureus endocarditis, both teicoplanin and vancomycin sterilized the vegetations of some rabbits, but the relapse rate was high for both. These results justify further investigation into the role of teicoplanin for the treatment of serious infections caused by S. aureus.     

Ciprofloxacin versus vancomycin in the therapy of experimental methicillin-resistant Staphylococcus aureus endocarditis.

We compared the efficacy of ciprofloxacin with that of vancomycin by using the rabbit model of methicillin-resistant Staphylococcus aureus endocarditis. Endocarditis was treated with ciprofloxacin (25 mg/kg [body weight] intravenously every 8 h) or vancomycin (17.5 mg/kg intravenously every 6 h) for 3 days. Vancomycin and ciprofloxacin were equally efficacious in clearing bacteremia. Both reduced vegetation bacterial counts by 5 log10 CFU/g and renal and splenic bacterial counts by more than 3 log10 CFU/g as compared with untreated control rabbits after 26 h of infection (P less than 0.001). Both antimicrobial agents were able to eradicate the infectious process in an equivalent proportion of animals. No methicillin-resistant S. aureus that was recovered from ciprofloxacin-treated rabbits developed resistance to ciprofloxacin during therapy. Peak concentrations of ciprofloxacin in the sera of rabbits with endocarditis were significantly higher than those predicted by single-dose studies in uninfected rabbits. This finding was likely due to changes in the pharmacokinetics of the drug with multiple dosing and in infected versus uninfected rabbits. This study demonstrated that intravenously administered ciprofloxacin is as efficacious as vancomycin is in an in vivo model of a serious systemic methicillin-resistant S. aureus infection.     

Efficacy of daptomycin in experimental endocarditis due to methicillin-resistant Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus is becoming increasingly prevalent as both a nosocomial and a community-acquired pathogen. Daptomycin, a lipopeptide antibiotic now in phase III clinical trials, is rapidly bactericidal in vitro against a range of gram-positive organisms, including methicillin-resistant S. aureus (MRSA). In this study, we compared the efficacy of daptomycin with that of vancomycin, each with or without rifampin, in a model of experimental aortic valve endocarditis due to MRSA. The infecting strain (MRSA strain 32) was susceptible to daptomycin (MIC = 1 micro g/ml), vancomycin (MIC = 0.5 micro g/ml), and rifampin (MIC = 0.5 micro g/ml). Daptomycin was administered at 25 or 40 mg/kg q24h (q24h) by subcutaneous injection in an attempt to simulate human doses of 4 and 6 mg/kg q24h, respectively. Vancomycin was given at 150 mg/kg q24h by continuous intravenous infusion. Rifampin was given at 25 mg/kg by intramuscular injection q24h. Treatment was started 6 h postinoculation and continued for 4.5 days. Outcome was assessed by counting the residual viable bacteria in vegetations. The mean peak daptomycin levels in serum at 2 h after subcutaneous administration of 25 and 40 mg/kg were 64 and 91 micro g/ml, respectively. Daptomycin was undetectable in serum at 24 h. The total exposure was comparable to that achieved clinically in humans receiving the drug. Bacterial counts (mean log(10) number of CFU per gram +/- the standard deviation) in untreated controls reached 10.6 +/- 0.8. In treated rats, bacterial counts were as follows: vancomycin, 7.1 +/- 2.5; daptomycin at 25 mg/kg, 5.5 +/- 1.7; daptomycin at 40 mg/kg, 4.2 +/- 1.5. The difference between daptomycin at 40 mg/kg and vancomycin at 150 mg/kg was statistically significant (P = 0.004). In the study of combination therapy, vegetation bacterial counts were as follows: daptomycin at 40 mg/kg, 4.6 +/- 1.6; rifampin, 3.6 +/- 1.3; vancomycin plus rifampin, 3.3 +/- 1.1; daptomycin plus rifampin, 2.9 +/- 0.8. The difference between daptomycin and daptomycin plus rifampin was statistically significant (P = 0.006). These results support the continued evaluation of daptomycin for serious MRSA infections, including infective endocarditis.     

Efficacy of fosfomycin in experimental osteomyelitis due to methicillin-resistant Staphylococcus aureus

The activity of fosfomycin was evaluated in an experimental methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis model. Eighteen rats were treated for 4 weeks with 150 mg of fosfomycin/kg of body weight intraperitoneally once daily or with saline placebo. After treatment, animals were euthanized and the infected tibiae were processed for quantitative bacterial culture. Bone cultures were positive for methicillin-resistant S. aureus in all 9 (100%) untreated controls and in 2 of 9 (22.2%) fosfomycin-treated rats. Thus, fosfomycin treatment was significantly more efficacious than placebo. No development of resistance was observed after the 4-week treatment period.     

Chronic osteomyelitis caused by Staphylococcus aureus: controlled clinical trial of nafcillin therapy and nafcillin-rifampin therapy

A controlled trial of treatment of chronic osteomyelitis caused by Staphylococcus aureus compared nafcillin alone with nafcillin plus rifampin for a six-week period. Treatment was well tolerated, the only adverse effect being mild neutropenia in four of 18 patients; no toxicity was observed from rifampin. Eight of ten patients in the combined treatment group had a favorable clinical response (with follow-up of two to four years) as compared to four of eight in the nafcillin group (P = .2). Despite the failure to show a statistically significant advantage of rifampin plus nafcillin, we conclude that the combination, along with appropriate surgery, should be considered for patients with chronic staphylococcal osteomyelitis.     

Failure of medical therapy in tricuspid endocarditis due to Staphylococcus aureus

A patient with isolated tricuspid endocarditis due to Staphylococcus aureus had persistent bacteremia despite antibiotic therapy for 47 days until surgery. Cultures of the resected valve disclosed 1.4 X 10(8) colony forming units per gram of valve. Time-kill studies done with the strain of S. aureus and the antibiotics used in the therapy of this patient disclosed decreased bactericidal activity of these antibiotics with increasing inocula concentrations. At 10(8) inoculum, only the combination of vancomycin and tobramycin was bactericidal. The inoculum dependence of bactericidal activity might explain the lack of correlation between in vitro susceptibility tests with clinical outcome of some endocarditis patients.     

Comparative efficacy of daptomycin and vancomycin in the therapy of experimental foreign body infection due to Staphylococcus aureus

The therapeutic activity of daptomycin was compared with that of vancomycin in a rat model of subcutaneously implanted tissue cages chronically infected with strain Rev1, a spontaneous methicillin-susceptible revertant of the methicillin-resistant Staphylococcus aureus strain MRGR3, showing equivalent virulence to its parent. The MIC and MBC of daptomycin (in Mueller-Hinton broth supplemented with 50 mg/L Ca2+) or vancomycin for strain Rev1 were 1-2 and 2-4 or 1 and 2 mg/L, respectively. In vitro elimination of strain Rev1 in the presence of 50% tissue cage fluid was more rapid with daptomycin 4 mg/L compared with vancomycin. After 2 weeks of infection, viable counts of strain Rev1 averaged 6.49 log10 cfu/mL of tissue cage fluid (n = 87). Intraperitoneal administration of daptomycin 30 mg/kg once daily, or vancomycin 50 mg/kg twice daily, produced antibiotic levels continuously above MBC. After 7 days of therapy with daptomycin or vancomycin, mean +/- S.E.M. counts of Rev1 decreased (P < 0.05) by 1.11 +/- 0.25 (n = 28) or 0.80 +/- 0.31 (n = 35) log10 cfu/mL, respectively, compared with cages of untreated animals, but were not significantly different from each other. In daptomycin-treated rats, three cages yielded subpopulations with reduced susceptibility to daptomycin. In conclusion, a low dose regimen of daptomycin was at least equivalent to vancomycin against chronic foreign body infections due to S. aureus. Drug dosage should be adapted to obtain inflammatory fluid levels of daptomycin minimizing emergence of resistant subpopulations.     

Linezolid therapy of Staphylococcus aureus experimental osteomyelitis

The in vivo activity of linezolid or cefazolin against a clinical isolate of methicillin-susceptible Staphylococcus aureus (linezolid MIC, 2 microg/ml) was studied in a rat model of experimental osteomyelitis. Sixty rats with experimental S. aureus osteomyelitis were treated for 21 days with no antimicrobial, with 25 microg of linezolid per kg of body weight administered intraperitoneally twice or three times a day, or with 50 microg of cefazolin per kg administered intramuscularly three times a day. After treatment, the animals were sacrificed and the infected tibiae were processed for quantitative bacterial cultures. The results of treatment were expressed as log(10) CFU/gram of bone and analyzed by rank sum analysis. The results of linezolid treatment were not significantly different from those of untreated controls, while cefazolin treatment was significantly more active than no treatment or linezolid treatment.     

Successful therapy of experimental chronic foreign-body infection due to methicillin-resistant Staphylococcus aureus by antimicrobial combinations.

We compared the efficacy of a long-duration (3-week) therapy of vancomycin, fleroxacin, fleroxacin plus rifampin, and vancomycin plus fleroxacin and rifampin in a recently developed rat model of chronic staphylococcal foreign-body infection. Subcutaneous tissue cages containing polymethylmethacrylate coverslips were infected with 1 x 10(5) to 5 x 10(5) CFU of methicillin-resistant Staphylococcus aureus. Three weeks later, a quantitative culturing of the fluid that had accumulated in the cages was done (mean, 6.72 log10 CFU/ml; n = 110) and treatment was initiated after randomization. The CFUs in the cage fluid were counted on days 11 and 22 and 1 week after the termination of treatment; in addition, a final culture of coverslips (surface-bound microorganisms) was performed. The three-drug therapy was significantly superior to the other treatments on day 11 (a 5.16 log10 decrease of bacterial counts versus a 2.12 log10 to 2.94 log10 decrease for vancomycin, fleroxacin, and fleroxacin plus rifampin; P less than 0.01). On day 22, count decreases were 4.16 log10 for vancomycin, 4.91 log10 for fleroxacin (vancomycin versus fleroxacin, not significant), 6.14 log10 for two-drug therapy, and 6.34 log10 for three-drug therapy (vancomycin-fleroxacin-rifampin versus fleroxacin-rifampin, not significant; fleroxacin-rifampin versus monotherapies, P less than 0.01); the numbers of CFU in most cage fluids were under the detection limit (20 CFU/ml) in combination groups. One week after the end of treatment, 92% of fluids and coverslips (detection limit, 1 CFU) were culture negative with tritherapy, 88% of fluids and 41% of coverslips were negative with bitherapy, and less than 12% of fluids and coverslips were negative with single drugs (for coverslips, P was <0.01 for vancomycin-fleroxacin-rifampin versus fleroxacin-rifampin and P was <0.001 for fleroxacin-rifampin versus the monotherapies). No mutants resistant to rifampin or fleroxacin were detected. In conclusion, antimicrobial combinations were highly effective and superior to single drugs in treating a chronic staphylococcal foreign-body infection for 3 weeks. The three-drug therapy decreased bacterial counts more rapidly than the two-drug therapy under study and appeared to be curative in most cases.     

Dexamethasone as adjuvant therapy to moxifloxacin attenuates valve destruction in experimental aortic valve endocarditis due to Staphylococcus aureus

Although the beneficial effects of dexamethasone have frequently been investigated in various serious-infection settings, insufficient data on valve histology and cardiac function for infective endocarditis are available. The efficacy of moxifloxacin for the treatment of experimental aortic valve endocarditis due to methicillin-susceptible Staphylococcus aureus and the long-term effects of dexamethasone were evaluated in the current study. Sixty-eight rabbits were randomly assigned to four groups: A, B, C, and D. Group A consisted of 18 animals and functioned as a control group. Groups B and C consisted of 11 and 23 subjects, respectively, which received moxifloxacin for 5 days in a human-like pharmacokinetic simulation. Group D consisted of 16 animals that were administered moxifloxacin plus dexamethasone (0.25 mg/kg of body weight twice a day intravenously). The group B animals were sacrificed a day after the completion of treatment, and group C and D animals were sacrificed after 12 days in order to monitor any possible relapse and allow microbiological, histopathological, and echocardiographic evaluation of the long-term effects of glucocorticoids. No differences in survival, sterilization rates, or inflammatory infiltration and calcification of valve tissue were observed among the treated groups. However, the degrees of valve damage and collagenization were significantly worse, the fibroblast content was higher, and fractional shortening of the left ventricle fluctuated significantly in group C compared to group D (all groups, P < 0.05). We concluded that dexamethasone treatment for experimental S. aureus endocarditis attenuates valve destruction and preserves overall cardiac function without impeding the efficacy of moxifloxacin.     

Efficacy of telavancin in the treatment of experimental endocarditis due to glycopeptide-intermediate Staphylococcus aureus

The efficacy of telavancin, a novel lipoglycopeptide, was evaluated in experimental endocarditis in rabbits using two clinical isolates of glycopeptide-intermediate Staphylococcus aureus: ATCC 700788 and HIP 5836. Infected rabbits were treated for 2 days with telavancin (10 mg/kg of body weight once daily intravenously) or vancomycin (1 g twice daily intravenously), administered with a computer-controlled infusion pump system simulating human serum kinetics. Vegetations were harvested at 16 h postinoculation in the control group and at the end of treatment in the drug-treated group. For ATCC 700788, MICs and minimal bactericidal concentrations (MBCs), respectively, were 1 mg/liter and 4 mg/liter for telavancin and 8 mg/liter and 128 mg/liter for vancomycin. For HIP 5836, MICs and MBCs, respectively, were 4 mg/liter and 8 mg/liter for telavancin and 8 mg/liter and 128 mg/liter for vancomycin. Peak and trough levels were 90 microg/ml and 6 microg/ml, respectively, for telavancin and 46 microg/ml and 6 microg/ml, respectively, for vancomycin. In glycopeptide-intermediate S. aureus ATCC 700788, telavancin sterilized 6 of 16 vegetations (37%), whereas vancomycin sterilized 4 of 20 (20%) (P = 0.29) compared with 0 of 17 in the control group. In HIP 5836 experiments, telavancin and vancomycin sterilized 5 of 16 (31%) and 1 of 15 (7%) vegetations (P = 0.17), respectively, compared with none in the control group. Telavancin reduced vegetation titers by 2.0 and 2.3 logs greater than vancomycin for the ATCC 700788 (4.6 [2.0 to 5.8] versus 6.6 [2.0 to 6.9] log CFU/g vegetation; P = 0.05) and HIP 5836 (4.4 [2.0 to 7.4] versus 6.7 [4.5 to 8.7] log CFU/g vegetation; P = 0.09) strains, respectively; these differences did not reach statistical significance. All isolates from vegetations remained susceptible to telavancin after therapy. The results suggest that telavancin may be an effective treatment for endocarditis caused by glycopeptide-intermediate S. aureus.     

Comparative evaluation of A-56619, A-56620, and nafcillin in the treatment of experimental Staphylococcus aureus osteomyelitis

A rabbit model for Staphylococcus aureus osteomyelitis was used to compare the results of treatment with A-56619 and A-56620, two new aryl-fluoroquinolones, and nafcillin. A-56619 (15 mg/kg) and A-56620 (20 mg/kg), both used for 28 days of treatment, were injected subcutaneously every 12 h, and nafcillin (40 mg/kg) was injected every 6 h. After treatment, S. aureus was found on bone marrow cultures from 19 of 20 control rabbits, 6 of 20 treated with A-56619, 14 of 20 treated with A-56620, and 8 of 20 treated with nafcillin. Drug concentrations in serum and uninfected and infected bone were measured 1 h after A-56619 and A-56620 injection and 30 min after nafcillin injection in a group of rabbits that had been infected for 3 to 4 weeks. The concentrations in infected bone were similar for all three drugs and were significantly higher than in uninfected bone. The results of this study showed that A-56619 had a high rate of eradication of S. aureus from infected bone and compared favorably to nafcillin.     

Comparative evaluation of oral levofloxacin and parenteral nafcillin in the treatment of experimental methicillin-susceptible Staphylococcus aureus osteomyelitis in rabbits

Methicillin-susceptible Staphylococcus aureus (MSSA) is the most common pathogen recovered from osteomyelitis patients. The current standard therapeutic method for acute phase osteomyelitis is parenteral antibiotic therapy. However, parenteral administration has negative aspects, such as secondary infection, patient inconvenience and high cost. The use of single oral antibiotic therapy may alleviate these problems. Therefore, the purpose of this study was to compare the effectiveness of standard once per day dosing of oral levofloxacin with a standard parenteral antibiotic regimen (nafcillin four times daily) for the treatment of experimental MSSA osteomyelitis in rabbits. Nearly all tibias from untreated infected controls (n = 27) revealed positive cultures (93%) for S. aureus, while the levofloxacin-treated group (n = 20) demonstrated significantly lower percentages of S. aureus infection (50%). The infected tibias of the nafcillin-treated group (n = 20) demonstrated significantly lower percentages (10%) of infected tibias than either the controls or the levofloxacin-treated groups (P < 0.05). The inferior efficacy of levofloxacin may have been due to the pharmacokinetic profile of this fluoroquinolone. The serum kinetics demonstrated that following single dose administration, levofloxacin was almost undetectable after 12 h. Studies in which levofloxacin is dosed every 12 h or given at increased doses in order to obtain bactericidal concentrations throughout the treatment regimen are needed.     

Oral temafloxacin versus vancomycin for therapy of experimental endocarditis caused by methicillin-resistant Staphylococcus aureus

We compared oral temafloxacin, a new fluoroquinolone agent, with vancomycin, each with and without rifampin, in the therapy of rats with aortic valve endocarditis caused by a clinical isolate of methicillin-resistant Staphylococcus aureus. The temafloxacin, vancomycin, and rifampin MICs and MBCs were 0.78 and 1.56, 1.56 and 3.13, and less than 0.024 and 0.78 microgram/ml, respectively. The animals were classified into the following six treatment groups: vancomycin (60 mg/kg) +/- rifampin (6 mg/kg) each intramuscularly every 12 h for 5 days; temafloxacin (100 mg/kg) orally +/- rifampin (6 mg/kg) intramuscularly every 12 h for 5 days; rifampin (6 mg/kg) intramuscularly every 12 h for 5 days; and untreated controls. All regimens with either vancomycin or temafloxacin resulted in improved survival over controls, but only temafloxacin regimens resulted in a significant reduction in bacterial counts in vegetations. These data support further investigation of the efficacy of temafloxacin in treating serious infections caused by methicillin-resistant S. aureus.     

Clindamycin therapy of experimental Staphylococcus aureus endocarditis.

The efficacy of clindamycin in the treatment of experimental endocarditis in rabbits was compared with that of nafcillin. Both drugs were administered intramuscularly three times daily for 5 days, clindamycin at doses of 6.25, 12.5, 25, or 50 mg/kg and nafcillin at a dose of 200 mg/kg. The minimum inhibitory and bactericidal concentrations (0.125 microgram/ml) of clindamycin for the test strain of Staphylococcus aureus were very similar to the corresponding concentrations (0.25 microgram/ml) of nafcillin. The effectiveness of clindamycin against the experimental endocarditis was dose dependent. The therapeutic accomplishments of the two highest clindamycin doses were equivalent to those attained with 200 mg of nafcillin per kg. The rates of sterilization of vegetations were equal when the serum bactericidal titers of these drugs were greater than or equal to 1:8. In special situations the administration of clindamycin in high doses could prove useful in the treatment of S. aureus endocarditis.     

Efficacy of daptomycin-cloxacillin combination in experimental foreign-body infection due to methicillin-resistant Staphylococcus aureus

Despite the use of daptomycin alone at high doses (greater than 6 mg/kg of body weight/day) against difficult-to-treat infections, clinical failures and resistance appeared. Recently, the combination daptomycin-cloxacillin showed enhanced efficacy in clearing bacteremia caused by methicillin-resistant Staphylococcus aureus (MRSA). The aim of this study was to evaluate the efficacy of daptomycin at usual and high doses (equivalent to 6 and 10 mg/kg/day in humans, respectively) in combination with cloxacillin in a rat tissue cage infection model by MRSA and to compare its efficacy to that of daptomycin-rifampin. We used MRSA strain ATCC BAA-39. In the log- and stationary-phase kill curves, daptomycin-cloxacillin improved the bactericidal activity of daptomycin, especially in log phase. For in vivo studies, therapy was administered intraperitoneally for 7 days with daptomycin at 100 mg/kg/day and 45/mg/kg/day (daptomycin 100 and daptomycin 45), daptomycin 100-cloxacillin at 200 mg/kg/12 h, daptomycin 45-cloxacillin, and daptomycin 100-rifampin at 25 mg/kg/12 h. Daptomycin-rifampin was the best therapy (P < 0.05). Daptomycin 45 was the least effective treatment and did not protect against the emergence of resistant strains. There were no differences between the two dosages of daptomycin plus cloxacillin in any situation, and both protected against resistance. The overall effect of the addition of cloxacillin to daptomycin was a significantly greater cure rate (against adhered bacteria) than that for daptomycin alone. In conclusion, daptomycin-cloxacillin enhanced modestly the in vivo efficacy of daptomycin alone against foreign-body infection by MRSA and was less effective than daptomycin plus rifampin. The benefits of adding cloxacillin to daptomycin should be especially evaluated against infections by rifampin-resistant MRSA and for protection against the emergence of daptomycin nonsusceptibility.     

Comparison of ceforanide, cefazolin, methicillin, and nafcillin in Staphylococcus aureus endocarditis therapy in rabbits.

Ceforanide (30 mg/kg) administered every 12 h, cefazolin (20 mg/kg) administered every 8 h and methicillin or nafcillin (40 mg/kg) administered every 6 h were equally effective in reducing the number of Staphylococcus aureus in vegetations in rabbits with endocarditis. These treatments were more effective than methicillin or nafcillin administered every 12 h. Ceforanide produced higher peak concentrations and greater bactericidal activity in serum than the other drugs and had the longest half-life (5.8 h, compared with 0.4 to 0.8 h for the other agents.     

Fusidic acid alone or in combination with vancomycin for therapy of experimental endocarditis due to methicillin-resistant Staphylococcus aureus.

The usefulness of fusidic acid, alone or combined with vancomycin, was investigated for the therapy of experimental endocarditis caused in rabbits by a methicillin-resistant strain of Staphylococcus aureus. In vitro killing curves showed an indifferent interaction between the two antibiotics. In vivo, vancomycin alone was as effective as a vancomycin-fusidic acid combination (P < 0.05 versus control animals). No resistance to fusidic acid emerged during combination therapy. Fusidic acid alone was not effective. Resistance emerged in 5 of 12 animals treated with fusidic acid alone and was responsible for antibacterial failure. Fusidic acid alone was effective (P < 0.001) and did not select resistant strains if therapy was started when animals retained a smaller inoculum. We concluded that the vancomycin-fusidic acid combination exhibited no advantage over vancomycin alone in this model.     

Failure of vancomycin continuous infusion against experimental endocarditis due to vancomycin-intermediate Staphylococcus aureus

Continuous infusion of vancomycin was evaluated against experimental endocarditis due to heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) and VISA. Animals were infected with hVISA PC1 (vancomycin MIC, 2 mg/liter) or VISA PC3 (vancomycin MIC, 8 mg/liter) and treated for 5 days with constant serum levels of 20 or 40 mg/liter. Vancomycin continuous infusion was unsuccessful, as 20 mg/liter was barely active against PC1 (6 of 13 sterile vegetations) and 40 mg/liter failed against PC3 (2 of 9 sterile vegetations).