Pharmacokinetic Profile of Trimethoprim-Sulfamethoxazole in Man

Kaplan, Stanley A.; Weinfeld, Robert E.; Abruzzo, Charles W.; McFaden, Kenneth; Jack, M.L.; Weissman, Lester

doi:10.1093/infdis/128.supplement_3.s547

Cited by 96 publications

(64 citation statements)

References 3 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“…It is likely that this represents rapid elimination of this compound in mice as we have determined (unpublished) that in Balb/c mice, the genetic background of the scid mice used in the present study, trimethoprim has a T l/2 of approximately 2 h in serum or lung lavage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: 80%

“…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: 80%

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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: 80%

Section: Discussionmentioning

confidence: 80%

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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“…Trimethoprim (TMP) and the sulphonamides in the current antibacterial combinations are characterized by considerably longer half-lives than most other antibiotics. In subjects with normal renal function the range of mean t 1 values was 9 to 14 h for TMP, 9 to 11 h sulphamethoxazole (SMZ) Kaplan et al, 1973;Zech et al, 1978), 10 to 15 h for sulfadiazine (SDZ) (Andreasen et al, 1978;Ohnhaus & Spring, 1975) and 9 to 11 h for sulfamoxole (SMO) (Kuhne et al, 1976). The obvious advantage of the relatively slow elimination is the possibility to maintain therapeutic serum levels by administration every 12 h. Besides being practical, this dosage regimen also prevents abnormal drug accumulation.…”

Section: Half-life and Drug Accumulationmentioning

confidence: 99%

“…Urinary elimination of unchanged drug in patients with normal renal function amounts to 53 to 67% for TMP Kaplan et al, 1973;, 15-30% for SMZ Kaplan et al, 1973;Ohnhaus & Spring, 1975), 50 to 54% for SDZ (Andreasen et al, 1978;Ohnhaus & Spring, 1975) and 34% for SMO (Kuhne et al, 1976). Most of the metabolites are pharmacologically inactive.…”

Section: Modes Of Eliminationmentioning

confidence: 99%

Pharmacokinetics of long half-life antibacterials

Folláth

1979

Journal of Antimicrobial Chemotherapy

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Trimethoprim (TMP), sulfamethoxazole (SMZ) and sulfadiazine (SDZ) are characterized by elimination half-lives of 9 to 15 h. Effective serum concentrations can therefore be maintained by twice daily administration, but without a loading dose steady state levels will be reached only after 3 days. Renal disease has little effect on the pharmacokinetics of unchanged SMZ, whereas TMP and SDZ elimination is prolonged in uremia. Dosage adaptation to creatinine clearance is difficult, since the ratio of the two components in serum and urine will be altered. Abnormal drug accumulation in liver disease during a treatment with TMP and SMZ has not been demonstrated.Die Halbwertszeiten von Trimethoprim (TMP), Sulfamethoxazol (SMZ) und Sulfadiazin (SDZ) liegen zwischen 9 und 15 h. Dank dieser 1angsamen Elimination konnen therapeutisch wirksame Serumkonzentrationen durch 12-stiindliche Medikamentengaben aufrecht erhalten werden. Ein 'steady-state' wird allerdings erst nach 3 Tagen erreicht, weshalb eine initiale Sattigungsdosis erforderlich sein kann. Bei Niereninsuffizienz bleibt die Halbwertszeit des SMZ unverandert, wogegen die Elimination des TMP und des SDZ bei Uramie verzogert sind. Bei den f1xen TMP/SMZ-Kombinationen ist eine Dosisanpassung bei stark verminderter Kreatinin-Clearance problematisch, da das Verhaltnis der einzelnen Komponenten infolge ihrer unterschiedlichen Kinetik gegeniiber der Norm verandert wird. Eine abnorme Akkumulation dieser Medikamente bei Leberkrankheiten wurde hingegen bis jetzt nicht beobachtet.

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“…With the latter two agents, synergism occurred at concentrations barely attainable in blood (8). However, urinary levels of TMP and SMZ with standard doses easily exceed these concentrations (19).…”

mentioning

confidence: 99%

Outbreak of Multiply Drug-Resistant Proteus mirabilis Originating in a Surgical Intensive Care Unit: In Vitro Susceptibility Pattern

Yoshikawa

Shibata

Chow

et al. 1978

Antimicrob Agents Chemother

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A multiply drug-resistant strain of Proteus mirabilis was isolated from 14 patients on a surgical service. Antimicrobial susceptibility studies demonstrated that the organism was highly resistant to numerous antibiotics, including gentamicin, tobramycin, and sisomicin. The organism was susceptible in vitro to amikacin but had low-level resistance to netilmicin. In vitro susceptibility studies with combinations of cephalothin with netilmicin and trimethoprim with sulfamethoxazole showed these drugs to be synergistic. Other drug combinations failed to act synergistically.

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Pharmacokinetic Profile of Trimethoprim-Sulfamethoxazole in Man

Cited by 96 publications

References 3 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

Pharmacokinetics of long half-life antibacterials

Outbreak of Multiply Drug-Resistant Proteus mirabilis Originating in a Surgical Intensive Care Unit: In Vitro Susceptibility Pattern

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