Ciprofloxacin therapy of experimental endocarditis caused by methicillin-resistant Staphylococcus epidermidis.

Ciprofloxacin or rifampin was significantly (P less than 0.05) more effective than vancomycin or the combination of vancomycin plus gentamicin for the treatment of Staphylococcus epidermidis experimental endocarditis. There were no significant differences in efficacy among any of the combinations of antimicrobial agents that included ciprofloxacin or rifampin. One animal treated with rifampin alone and one treated with the combination of vancomycin, rifampin, and gentamicin were found to be infected with rifampin-resistant strains of S. epidermidis during therapy. Resistant subpopulations of S. epidermidis were not detected during therapy with any other antimicrobial agent used alone or in combination. Ciprofloxacin alone or in combination with rifampin was effective therapy against S. epidermidis experimental endocarditis.     

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.     

Lack of extracellular slime effect on treatment outcome of Staphylococcus epidermidis experimental endocarditis

We studied the response of two slime negative Staphylococcus epidermidis strains (NS1 and NS2) and one slime producing strain (S1) to treatment with vancomycin in the rabbit catheter-induced endocarditis model. All micro-organisms had vancomycin minimal inhibitory concentration and minimal bactericidal concentration of 4 mg/l. Three days after infection, treatment with vancomycin 25 mg/kg every 12 h was begun and continued for 4 days. Cardiac valve vegetations were harvested 12 h after the last dose of vancomycin and cultured quantitatively. In treated animals the mean +/- S.D. log10 colony forming units per g of cardiac valve vegetation were 1.6 +/- 0.1 for NS1, 4.4 +/- 1.9 for NS2, and 2.3 +/- 1.2 for S1. Slime production did not influence the results of vancomycin therapy of S. epidermidis experimental endocarditis. Other factors may cause strain-dependent variability in response to antimicrobial treatment in this model.     

Staphylococcus epidermidis endocarditis: a community-acquired methicillin-resistant isolate

We have described a patient with community-acquired, methicillin-resistant Staphylococcus epidermidis endocarditis that occurred on a prolapsing mitral valve. The patient was successfully treated with vancomycin and rifampin for six weeks and had no signs of relapse four months later.     

Ciprofloxacin therapy of experimental endocarditis caused by methicillin-susceptible or methicillin-resistant Staphylococcus aureus.

Ciprofloxacin was more effective (P less than 0.01) than either imipenem or nafcillin therapy of experimental methicillin-susceptible Staphylococcus aureus endocarditis in rabbits after 2 or 3 days of treatment. There was no significant difference between results of treatment of methicillin-susceptible S. aureus experimental endocarditis with ciprofloxacin and results with the combination of nafcillin and gentamicin. Ciprofloxacin was more effective (P less than 0.01) than vancomycin therapy of experimental methicillin-resistant S. aureus endocarditis after 3 days of treatment. After 5 days of treatment, there was no significant difference between the results of treatment of experimental methicillin-resistant S. aureus endocarditis with ciprofloxacin and results with vancomycin.     

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.     

Antibiotic activity in vitro against methicillin-resistant Staphylococcus epidermidis and therapy of an experimental infection.

Staphylococcus epidermidis is a major pathogen in early prosthetic valve endocarditis and cerebrospinal fluid shunt infections. Approximately 10 to 15% of hospital isolates are methicillin resistant. Ten clinically significant isolates of the latter were collected for antibiotic studies in vitro and in an experimental infection in animals. Time-kill studies of five strains showed gentamicin to be the single most effective antibiotic; however, dwarf colony variants emerged as survivors with two of these strains when challenged with gentamicin alone. The addition of a second antibiotic to gentamicin did not significantly improve the bactericidal rate but prevented the emergence of variant strains. A blood culture isolate of methicillin-resistant S. epidermidis combined with 5% hog gastric mucin was used to establish an experimental intraperitoneal infection in mice. Neither methicillin nor nafcillin treatment reduced mortality below that of untreated animals. Cephalothin treatment delayed early mortality but did not diminish overall mortality. Gentamicin was the most effective single antibiotic, and gentamicin in combination with vancomycin was the most effective regimen overall. The combination of rifampin plus vancomycin was as effective as gentamicin alone. The combinations of cephalothin or nafcillin with gentamicin and cephalothin with vancomycin demonstrated antagonism. The antagonism was not due to multiple injections or drug-drug inactivation.     

Comparison of cefazolin, cefamandole, vancomycin, and LY146032 for prophylaxis of experimental Staphylococcus epidermidis endocarditis.

We evaluated antibiotic prophylaxis in the rabbit model of experimental endocarditis with three strains of Staphylococcus epidermidis of differing susceptibility patterns. For the first strain, which was highly susceptible to methicillin and cephalosporins, vegetations grew S. epidermidis for all 15 untreated rabbits compared with 1 of 20 rabbits receiving cefazolin, 3 of 20 receiving cefamandole, none of 20 receiving vancomycin, and none of 20 receiving LY146032. For the second strain, which was methicillin resistant but cephalosporin susceptible, vegetations were positive for 14 of 15 untreated controls, 4 of 20 receiving cefazolin, 5 of 22 receiving cefamandole, none of 20 receiving vancomycin, and none of 20 receiving LY146032. For the third strain, which was methicillin resistant and only intermediately susceptible to cephalosporin antibiotics, vegetation cultures were positive for 15 of 17 untreated controls, 14 of 21 receiving cefazolin, 11 of 20 receiving cefamandole, 5 of 20 receiving vancomycin, and 0 of 22 receiving LY146032. In conclusion, these studies in the endocarditis model indicate that cefazolin and cefamandole have some protective value against certain strains of S. epidermidis. Vancomycin and LY146032, however, were more active than cephalosporins for all three strains included in this analysis. These findings support the need for trials of vancomycin and LY146032 prophylaxis in patients undergoing placement of prosthetic heart valves.     

Single- and combination-antibiotic therapy for experimental endocarditis caused by methicillin-resistant Staphylococcus aureus.

The efficacy of fosfomycin in combination with vancomycin or gentamicin was evaluated in experimental endocarditis caused by methicillin-resistant Staphylococcus aureus. After 5 days of therapy, both combinations proved to be highly effective since all rabbits had sterile vegetations.     

Development of resistance to fleroxacin during therapy of experimental methicillin-susceptible Staphylococcus aureus endocarditis.

The efficacy of fleroxacin was compared with that of vancomycin by using the rabbit model of methicillin-susceptible Staphylococcus aureus endocarditis. Animals received intravenous therapy with fleroxacin, 30 mg/kg every 8 h, or vancomycin, 17.5 mg/kg every 6 h, for 4 days. Both antimicrobial agents effectively cleared bacteremia and significantly reduced bacterial counts in vegetations and tissues compared with those in untreated controls. However, resistance to fleroxacin at 5- and 10-fold the MIC arose in the test strain of S. aureus in 73 and 27%, respectively, of animals that received the drug. Resistant isolates were found mainly in vegetations and were composed of up to 7% of the residual population recovered from that site. We conclude that fleroxacin is as effective as vancomycin in this model of a serious systemic S. aureus infection, but resistance to the drug may develop during therapy. If similar results are found with other strains of S. aureus during therapy with this or other fluoroquinolones, such data, when they are combined with the high incidence of fluoroquinolone resistance among S. aureus isolates being reported from selected institutions, would support the contention that these drugs should not be used as first-line therapeutic agents for S. aureus infections.     

Daptomycin compared with teicoplanin and vancomycin for therapy of experimental Staphylococcus aureus endocarditis.

The efficacies of daptomycin, teicoplanin, and vancomycin were compared in the therapy of experimental Staphylococcus aureus endocarditis. Rabbits infected with either of two methicillin-susceptible strains (SA-12871 or its moderately teicoplanin-resistant derivative SA-12873) or a methicillin-resistant S. aureus strain (MRSA-494) were treated with daptomycin, 8 mg/kg of body weight, every 8 h; teicoplanin, 12.5 mg/kg (low-dose teicoplanin [teicoplanin-LD], excluding MRSA-494) or 40 mg/kg (high-dose teicoplanin [teicoplanin-HD]) every 12 h; or vancomycin, 17.5 mg/kg every 6 h, for 4 days. Compared with no treatment daptomycin, teicoplamin-HD, and vancomycin significantly reduced bacterial counts of all test strains in vegetations and renal and splenic tissues (P less than 0.001). Teicoplanin-LD was equally effective against SA-12871 but failed against SA-12873, with three of six animals still being bacteremic at the end of therapy. For SA-12871, daptomycin was as effective as teicoplanin-HD and was superior to teicoplanin-LD and vancomycin (P = 0.02) in lowering vegetation bacterial counts. There were no differences between daptomycin, teicoplanin-HD, or vancomycin in the reduction of bacterial counts in tissues for any of the test strains. In rabbits infected with SA-12871, vegetations from 33% of teicoplanin-LD-treated, 6% of teicoplanin-HD-treated, and 13% of daptomycin-treated animals yielded organisms for which there were up to eightfold increases in the MICs. Resistance may have contributed to early death in one daptomycin-treated animal. No increases in the MICs for the test strain were detected in animals infected with SA-12873 or MRSA-494. We conclude that in this model and against these strains of S. aureus, daptomycin and teicoplanin-HD are as efficacious as vancomycin, but diminished susceptibility to both can develop during therapy.     

Methicillin-resistant Staphylococcus epidermidis.

Staphylococcus epidermidis is frequently associated with infection of prosthetic heart valves, prosthetic orthopedic devices, and neurosurgical shunts. Penicillinase-resistant semisynthetic penicillins, such as methicillin, have been the therapeutic and prophylactic agents of choice for S epidermidis infection. However, more S epidermidis isolates are now resistant to methicillin and other penicillins. In our laboratory 41% of S epidermidis isolates were resistant to methici-lin. All of the methicillin-susceptible isolates and 82% of the methicillin-resistant isoates were susceptible to cephalothin. Cephalothin should replace methicillin as the prophylactic and therapeutic agent of choice in institutions with a high percentage of methicillin-resistant S epidermidis.     

Efficacy of ofloxacin in experimental Staphylococcus aureus endocarditis.

The efficacy of ofloxacin was compared with that of vancomycin in the therapy of experimental Staphylococcus aureus endocarditis. Rabbits infected with either a methicillin-susceptible (MSSA-1199) or a methicillin-resistant (MRSA-494) test strain were treated with ofloxacin (20 mg/kg of body weight every 8 h) or vancomycin (17.5 mg/kg of body weight every 6 h) for 4 days. The antimicrobial agents were found to be equally effective in clearing bacteremia and in reducing bacterial counts in vegetations and in renal and splenic tissue of animals infected with either test strain. The drugs were of equal efficacy in curing MRSA-494 endocarditis. No resistance to ofloxacin emerged in either test strain during therapy. We conclude that in this model ofloxacin is as efficacious as vancomycin and that, unlike for other fluoroquinolones we have evaluated, resistance to the drug does not develop during therapy of this serious S. aureus infection.     

Pefloxacin therapy for experimental endocarditis caused by methicillin-susceptible or methicillin-resistant strains of Staphylococcus aureus.

The therapeutic efficacy of pefloxacin in experimental endocarditis caused by methicillin-susceptible or methicillin-resistant Staphylococcus aureus was evaluated. In rabbits infected with a methicillin-susceptible strain, 4 days of pefloxacin therapy significantly reduced both the number of bacteria per gram of vegetation and the mortality rate compared with untreated controls, and pefloxacin was equivalent to cephalothin. Pefloxacin was also as effective as vancomycin in reducing vegetation titers and mortality rate in animals with endocarditis caused by a methicillin-resistant strain. These results suggest that pefloxacin may be an effective agent in the therapy of serious infections caused by either methicillin-susceptible or -resistant strains of S. aureus.     

The effect of slime production on vancomycin efficacy in the treatment of experimental endocarditis due to Staphylococcus epidermidis

We compared the efficacy of vancomycin in the treatment of experimental endocarditis caused by either a parent strain of Staphylococcus epidermidis that produced slime or a daughter strain that produced less slime. After subcutaneously administered vancomycin, we noted similar cure rates and similar microbiological characteristics of endocardial infections in rats challenged with these strains, regardless of slime produced.     

Ampicillin therapy of experimental enterococcal endocarditis.

In rabbits with experimental enterococcal endocarditis, subcutaneously implanted perforated polyethylene chambers were used for ampicillin administration by intra-chamber injection. A total of 21 days of intra-chamber ampicillin therapy sterilized vegetations of 14 out of 14 rabbits with experimental enterococcal endocarditis. In rabbits treated for less than 21 days, the duration of therapy and quantitative vegetation cultures were inversely related. Peak serum minimal bactericidal titers were greater than or equal to 1:8 in 94% of the determinations. Trough serum minimal bactericidal titers were less than or equal to 1:2. The mean trough serum ampicillin concentration (2.6 micrograms/ml) was greater than the minimal bactericidal concentration of ampicillin for the infecting enterococcus and less than the mean trough chamber fluid ampicillin concentration (3.7 micrograms/ml). Relatively prolonged therapy with intrachamber injections seemed to be well tolerated. Combination drug therapy of enterococcal endocarditis may not always be required. The maintenance of serum minimal bactericidal titers greater than or equal to 1:8 throughout the therapy of endocarditis, as is often recommended, may be unnecessary.     

Efficacy of fleroxacin in experimental methicillin-resistant Staphylococcus aureus endocarditis.

The efficacy of fleroxacin versus that of vancomycin was assessed by using the rabbit model of methicillin-resistant Staphylococcus aureus endocarditis. Animals were treated with fleroxacin (30 mg/kg of body weight every 8 h) or vancomycin (17.5 mg/kg every 6 h) for 4 days. These antimicrobial agents were equally effective in clearing bacteremia, reducing bacterial counts in vegetations and tissues, and curing endocarditis. However, resistance to fleroxacin at fivefold the MIC arose in the test strain of S. aureus in 8% of animals that received the drug. We conclude that fleroxacin is as efficacious as vancomycin in this model of a serious systemic S. aureus infection, but modest resistance to fleroxacin may develop during therapy.     

Teicoplanin and rifampicin singly and in combination in the treatment of experimental Staphylococcus epidermidis endocarditis in the rabbit model

Teicoplanin and rifampicin were evaluated as single and combined agents in the treatment of endocarditis due to Staphylococcus epidermidis in the rabbit model. Rabbits were treated for ten days and the number of bacteria in vegetations determined. At the end of ten days the geometric mean number of bacteria in the vegetations were 5.53 X 10(8), 6.68 X 10(6). 1.10 X 10(4), 2.57 X 10(1) cfu/g of vegetation for control, teicoplanin, rifampicin, and teicoplanin plus rifampicin groups respectively. The MIC and MBC values of the S. epidermidis isolates were 0.78 mg/l for teicoplanin and less than or equal to 0.10 mg/l for rifampicin. In the rifampicin treated group three post-treatment isolates of S. epidermidis tested exhibited marked resistance to rifampicin with MIC and MBC values greater than or equal to 200 mg/l. Teicoplanin and rifampicin were both effective as single agents in the clearance of S. epidermidis from the bloodstream. Rifampicin was more effective than teicoplanin in the clearance of S. epidermidis from vegetations but teicoplanin in combination with rifampicin was more effective than either drug alone.     

Ciprofloxacin and rifampin, alone and in combination, for therapy of experimental Staphylococcus aureus endocarditis.

The therapeutic activities of ciprofloxacin (25 mg/kg every 8 h), rifampin (10 mg/kg every 24 h), ciprofloxacin plus rifampin, and vancomycin (17.5 mg/kg every 6 h) were compared by using the rabbit model of Staphylococcus aureus endocarditis. Animals infected with one of two test strains (SA1199 or SA487) were randomized into treatment groups and received 6 days of therapy. For SA1199, ciprofloxacin plus rifampin was most effective at reducing vegetation bacterial counts. For SA487, ciprofloxacin plus rifampin was as effective as vancomycin but less effective than ciprofloxacin alone. Resistance to ciprofloxacin at 5- and 10-fold the MIC emerged in the test strain in 82 and 55%, respectively, of rabbits infected with SA1199 and receiving ciprofloxacin monotherapy. The combination of ciprofloxacin and rifampin decreased these frequencies to 60% (P = 0.27) and 10% (P = 0.04). No resistance to ciprofloxacin was found in rabbits infected with SA487. We conclude that ciprofloxacin and ciprofloxacin plus rifampin are as efficacious as vancomycin in this model and that combining rifampin with ciprofloxacin may decrease the frequency at which high-level resistance to ciprofloxacin emerges. However, with respect to improved efficacy, the combination of ciprofloxacin and rifampin is unpredictable and may be detrimental.     

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.