Clinical Pharmacology of Intravenously Administered Trimethoprim-Sulfamethoxazole

Grose, William E.; Bodey, Gerald P.; Loo, Ti Li

doi:10.1128/aac.15.3.447

Cited by 60 publications

(29 citation statements)

References 18 publications

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“…It is likely that this represents rapid elimination of this compound in mice as we have determined (unpublished) that in Balb/c mice, the genetic background of the scid mice used in the present study, trimethoprim has a T l/2 of approximately 2 h in serum or lung lavage fluid following im or po administration of 100/500 mg/kg/day trimethoprim/sulphamethoxazole, whereas sulphamethoxazole has a T ip of about 20 h in serum and about 10 h in lung lavage fluid. Although the Ti n of sulphamethoxazole in Balb/c mice is similar to that in humans (8-6 h (Grose, Bodey & Loo, 1979); 11 h (Kaplan et al, 1973); 14 h (Stevens et al, 1991)), the T l/2 of trimethoprim in mice is considerably shorter than the Tip. of trimethoprim in humans (7-6 h (Grose et al, 1979); 11 h (Kaplan et al, 1973); 13-6 h (Stevens et al, 1991)).…”

Section: Discussionmentioning

confidence: 99%

“…Although the Ti n of sulphamethoxazole in Balb/c mice is similar to that in humans (8-6 h (Grose, Bodey & Loo, 1979); 11 h (Kaplan et al, 1973); 14 h (Stevens et al, 1991)), the T l/2 of trimethoprim in mice is considerably shorter than the Tip. of trimethoprim in humans (7-6 h (Grose et al, 1979); 11 h (Kaplan et al, 1973); 13-6 h (Stevens et al, 1991)). This confirms previous observations of rapid elimination of trimethoprim in rodents (Walzer et al, 1992a).…”

Section: Discussionmentioning

confidence: 99%

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The scid mouse as an experimental model for the evaluation of anti-Pneumocystis carinii therapy

Kunz¹,

Junker²,

Blaser³

et al. 1995

J Antimicrob Chemother

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The usefulness of scid mice bearing endogenous Pneumocystis carinii infection as a model for experimental chemotherapy was examined using standard compounds known to be effective against P. carinii. Trimethoprim/sulphamethoxazole was able to reduce pulmonary P. carinii cysts in a dose-dependent manner within the dose range studied (10/50 to 100/500 TMP/SMX mg/kg/d, bd, po, 5 days per week for 30 treatments). However, alterations in associated symptoms of infection (reduced body weight, increased lung weight, increased blood leucocytes and erythrocytes), was apparently not linearly dose-dependent. Blood and lung lavage fluid levels of sulphamethoxazole one hour post administration of trimethoprim/sulphamethoxazole was dose-dependent, but not linear with dose, and was apparently correlated to cyst reduction; trimethoprim was below the limit of detection at this time. Treatment of mice with 100/500 mg/kg/day trimethoprim/ sulphamethoxazole required 2 weeks (bd for 10 days of treatment) before changes in indices of infection became significant. Pentamidine (20 mg/kg, sc, three times per week for 3 weeks) was nearly as effective as high-dose trimethoprim/ sulphamethoxazole in reducing cysts, whereas lower doses were ineffective. Despite being unable to reduce pulmonary P. carinii infection, even low doses of pentamidine (6 or 2 mg/kg, sc, three times per week for 3 weeks) were able to reduce lung weights and blood leucocyte levels. This model of pulmonary P. carinii infections is amenable to chemotherapeutic intervention in an apparently dose-dependent fashion, and can be used to evaluate the capacity of compounds to eradicate P. carinii and resolve signs of infection.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The scid mouse as an experimental model for the evaluation of anti-Pneumocystis carinii therapy

Kunz¹,

Junker²,

Blaser³

et al. 1995

J Antimicrob Chemother

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“…Using Difco MHB, we found TMP-SMX to be bactericidal for each of 131 enterococcal isolates at s0.25 ,ug of TMP and 4.75 ,ug of SMX per ml, and we found TMP alone to be bactericidal for 92% of isolates at c0.5 ,uglml. The mean minimal steady-state serum levels for TMP and SMX when administered orally three times a day as the fixed-ratio combination at a dose containing 160 and 800 mg, respectively (one double-strength tablet), are 2.98 and 43.4 ,ug/ml (10); these values are approximately doubled after intravenous administration (9). Thus, serum levels are easily obtained which are 25-fold higher than the MBC of TMP-SMX for the least sensitive isolate tested and 75-fold higher than the mean MBC of 0.04 ,glml.…”

Section: Faecalismentioning

confidence: 92%

Susceptibility of enterococci to trimethoprim and trimethoprim-sulfamethoxazole

Crider¹,

Colby²

1985

Antimicrob Agents Chemother

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The in vitro activities of trimethoprim (TMP), alone and in combination with sulfamethoxazole (SMX), against 131 clinical isolates of enterococci, 126 Streptococcus faecalis isolates, and 5 Streptococcus faecium isolates were determined by a broth microdilution method with Mueller-Hinton broth that was substantially free of inhibitory substances. The geometric mean MIC of TMP for strains of S. faecalis was 0.164 ,g/ml (range, 0.03 to 8 ,g/ml), with a geometric mean MBC of 0.298 ,ug/ml (range, 0.063 to 8 ,ug/ml). Although all strains were resistant to the sulfonamide alone, the inhibitory and bactericidal activities of TMP against strains of S. faecalis were markedly potentiated when TMP was combined in a fixed ratio of 1:19 with SMX; the geometric mean MIC of TMP was reduced to 0.016 ,ug/ml (range, 0.002 to 0.25 ,ug/ml), with a geometric mean MBC of 0.031 ,ug/ml (range, 0.004 to 0.25 ,g/ml). The combination had no synergistic effect against strains of S. faecium; the geometric mean MICs and MBCs of both agents were ca. 0.06 ,ug/ml. The MBC/MIC ratios for TMP and TMP-SMX were .16 for all 131 strains. MICs and MBCs for TMP-SMX were unchanged, and for TMP they decreased when performed in broth supplemented with 50% heat-inactivated pooled human serum. For TMP ind TMP-SMX, the susceptibilities of isolates with high-level resistance to gentamicin or streptomycin were the same as those of isolates pusceptible to <2,000 ,ug of aminoglycoside per ml. These results suggest that tMP-SMX and TMP alone could prove useful in the treatment of serious enterococcal infections, including infections by strains with high-level resistance to aminoglycosides.The enterococci are important pathogens in endocarditis and urinary tract infections and are frequently isolated from polymicrobial infections (11). Because currently used antibiotics are not bactericidal against most strains of enterococci at concentrations readily achievable in the serum, optimal therapy for serious or deep-seated enterococcal infection includes the addition of an aminoglycoside to penicillin, ampicillin, or vancomycin for synergistic, bactericidal activity (20). The combination of a cell wall-active agent plus an atninoglycoside, however, is not synergistic against all strains of enterococci; these strains usually exhibit high-level resistance (MIC, >2,000 ,ug/ml) to the aminoglycoside (4), Recent studies have described clinical isolates of enterococci possessing high-level resistance to all currently available aminoglycosides (14, 15). The optimal therapy for serious infections caused by these strains is unknown.Trimethoprim (TMP) and the fixed-ratio combination of TMP and sulfamethoxazole (SMX) are effective against a broad spectrum of gram-negative and -positive organisms (1). The activities of these agents against enterococci, however, have varied subMtantially among different studies (2,5,12,18,24). These inconsistencies are due primarily to inhibitory substances present within the media that enable many species of bacteria to escape the action of TMP a...

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“…Pharmacokinetic studies were performed with uninfected control animals to estimate dosages of TMP required to obtain peak levels of about 3 to 5 g/ml, equivalent to those achieved during oral or parenteral therapy in humans (11,31). Blood samples were taken from rabbits with endocarditis on the second day of therapy 60 min after administration of antibiotics and just before the next dose to measure the peak and trough levels of antimicrobial agents.…”

Section: Methodsmentioning

confidence: 99%

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

Górgolas

Avilés

Verdejo

et al. 1995

Antimicrob Agents Chemother

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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 ...

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Clinical Pharmacology of Intravenously Administered Trimethoprim-Sulfamethoxazole

Cited by 60 publications

References 18 publications

The scid mouse as an experimental model for the evaluation of anti-Pneumocystis carinii therapy

The scid mouse as an experimental model for the evaluation of anti-Pneumocystis carinii therapy

Susceptibility of enterococci to trimethoprim and trimethoprim-sulfamethoxazole

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

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