Treatment of experimental endocarditis due to methicillin-susceptible or methicillin-resistant Staphylococcus aureus with trimethoprim-sulfamethoxazole and antibiotics that inhibit cell wall synthesis

Abstract

Using two strains of Staphylococcus aureus, one susceptible and one heterogeneously resistant to methicillin, for which MICs and MBCs of trimethoprim-sulfamethoxazole (TMP-SMX) were 0.06 and 0.06 g/ml and 0.06 and 0.25 g/ml, respectively (concentrations are those of TMP), we studied the efficacies of TMP-SMX and cloxacillin, teicoplanin, and vancomycin for treatment of experimental staphylococcal endocarditis. Rabbits were treated with dosages of TMP-SMX selected to achieve concentrations in serum equivalent to that obtained in humans treated for Pneumocystis carinii pneumonia. The overall mortality rate of rabbits treated with TMP-SMX was 84% at day 3, not different from that of the control groups (P > 0.1). No sterile vegetations were observed to be present in control groups or in animals treated with TMP-SMX. However, 26, 60, and 75% of rabbits treated with teicoplanin, cloxacillin, and vancomycin, respectively, showed sterile vegetations. For methicillin-susceptible S. aureus (MSSA), the mean vegetation counts were not significantly different between the control group and the group treated with TMP-SMX (P > 0.1). For methicillin-resistant S. aureus (MRSA), treatment with TMP-SMX was more effective than no therapy, decreasing the number of organisms in vegetations (P < 0.01). For both strains, therapy with cloxacillin and therapy with teicoplanin or vancomycin were significantly more effective than therapy with TMP-SMX. Despite high concentrations of teicoplanin in serum which exceeded MBCs for staphylococci more than 50 times at the peak and 10 times at the trough, therapy with cloxacillin or vancomycin was superior to therapy with teicoplanin against both MSSA and MRSA. These data do not support the use of TMP-SMX in treatment of endocarditis and other severe staphylococcal infections with high bacterial counts.Staphylococcus aureus remains an important cause of both uncomplicated and complicated bacteremic infections and is the leading cause of infectious endocarditis in many medical centers around the world (23, 30). Antimicrobial therapy of staphylococcal infections has become more troublesome because of the recent emergence and spread of methicillin-resistant S. aureus (MRSA) strains. Previous reports have documented an increased prevalence of MRSA in hospitals in the United States and Europe (3, 18), and there is at present a scarcity of effective antimicrobial regimens for these strains (12).Beta-lactam antibiotics alone or in combination with aminoglycosides are regarded as first-choice therapy for treatment of methicillin-susceptible S. aureus (MSSA) endocarditis, and vancomycin therapy is recommended for patients with penicillin allergies and for those with serious infections caused by MRSA, including endocarditis (19). However, several recent reports have shown suboptimal clinical outcome in patients with staphylococcal endocarditis treated with vancomycin (13, 16). For these reasons, a continuous search for alternative antimicrobial drugs is of paramount importance.In vitro, most strains of MRSA ...

Efficacy of Linezolid in Treatment of Experimental Endocarditis Caused by Methicillin-Resistant Staphylococcus aureus

“…Previous studies using identical doses and dosing intervals of vancomycin in a similar rabbit model of endocarditis reported a typical 1-h postdose peak level of vancomycin in plasma between 33 and 48 g/ml (5,7,12). The mean peak levels of vancomycin in plasma, 36.0 Ϯ 5.9 g/ml after the first dose and 38.4 Ϯ 12.5 g/ml after the last dose, are within the reported range for peak levels of vancomycin in plasma.…”

Efficacy of Iclaprim against Wild-Type and Thymidine Kinase-Deficient Methicillin-Resistant Staphylococcus aureus Isolates in an In Vitro Fibrin Clot Model

“…It also is known that the serum of rodents contains large concentrations of thymidine compared to human serum, i.e., Ն1 and Յ0.01 g/ml, respectively (3,27). Although not formally demonstrated, this is the most plausible reason as to why testing TMP or TMP-SMX against staphylococci in a rodent environment, both in vitro and in vivo, has been reported to result in failure (8,18).…”

“…TMP-SMX is advocated as a substitute therapy against TMP-SMX-susceptible MRSA in circumstances (1,32) where it is not overtly known to fail. However, TMP-SMX did poorly against experimental endocarditis due to MRSA in rabbits (8), which would have predicted treatment failures. The discordance between antistaphylococcal success in human clots and in human endocarditis and failure in rat clots and rabbit endocarditis studies may be explained by our observations.…”

“…Clots were washed three times with saline, weighed, and dissolved in 1 volume of trypsin solution (Sigma). Drug concentration in serum and in dissolved clots was determined by an agar diffusion assay with antibiotic medium 1 (Difco), using Bacillus subtilis ATCC 6633 as the indicator organism for iclaprim (this study) and vancomycin (9,10) and Bacillus pumilus CECT 510 as the indicator organism for TMP, which was used as a surrogate for TMP-SMX (8). Standard solutions were prepared in rat or human serum or in trypsinized clots.…”

“…Paradoxically, TMP-SMX tended to fail against MRSA experimental endocarditis in rabbits (8) and against experimental enterococcal endocarditis in rats (12). The poor activity of TMP-SMX in rodent models of endocarditis may be due in part to the bacterial uptake of exogenous thymidine and its conversion into thymidylate by thymidine kinase, a well-known bypass mechanism antagonizing the in vitro activity of TMP in certain microorganisms, including staphylococci and enterococci (14).…”