Pharmacokinetics of the Antibacterial Combination Sulfamethoxazole plus Trimethoprim in Patients with Normal or Impaired Kidney Function

Rieder, Josef; Schwartz, D E; Fernex, M; Bergan, Tom; Brodwall, E. K.; Blumberg, A; Cottier, P; Scheitlin, W

doi:10.1159/000395184

Cited by 52 publications

(39 citation statements)

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“…Although the systemic half-life of SMX and TMP in rodents is not known, based on the half-life in humans (9 h for SMX and 10 to 12 h for TMP), SMX-TMP should have been removed systemically prior to inoculation with Pneumocystis (61,62,67). However, the possibility exists that residual drug could remain in the intracellular compartment in the pulmonary tissues.…”

Section: Discussionmentioning

confidence: 99%

Combination Exposure to Zidovudine plus Sulfamethoxazole-Trimethoprim Diminishes B-Lymphocyte Immune Responses toPneumocystis murinaInfection in Healthy Mice

Feola

Garvy

2006

Clin Vaccine Immunol

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We have previously shown that zidovudine plus sulfamethoxazole-trimethoprim exposure decreases immune cell populations in the bone marrow of healthy mice by inducing apoptosis. The hypothesis of the current work was that this toxicity would have an adverse impact on the immune response. To determine this, BALB/c mice were treated with zidovudine, sulfamethoxazole-trimethoprim, the combination of both drugs, or vehicle only (control) via oral gavage for 21 days. On day 4 after dosing completion, the mice were infected intratracheally with 1 ؋ 10 7 Pneumocystis murina organisms. Immune cell populations (in lung digest, bronchoalveolar lavage fluid, tracheobronchial lymph node, and bone marrow samples), the lung Pneumocystis burden, and serum Pneumocystis-specific antibody titers were determined at days 6, 10, and 20 postinfection. While total bone marrow cellularity was recovered by day 6 postinfection in the combination exposure group, B-cell numbers did not recover until 10 days postinfection, primarily due to the persistent depletion of the late pre-B-cell phenotype. The numbers of CD4 ؉ and CD8 ؉ T cells, as well as the numbers of total B cells and activated B cells in tracheobronchial lymph nodes, were decreased at days 10 and 20 as a result of zidovudine plus sulfamethoxazole-trimethoprim exposure compared to the numbers in the control group. No significant differences in lung lavage or lung digest cell populations were observed. There was a trend of a delay in Pneumocystis clearance in the combination treatment group, and Pneumocystis-specific serum immunoglobulin G titers were reduced at day 20 postinfection. Together, these data indicate that the combination of zidovudine and sulfamethoxazole-trimethoprim adversely affects the humoral immune response to Pneumocystis.

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Section: Discussionmentioning

confidence: 99%

Combination Exposure to Zidovudine plus Sulfamethoxazole-Trimethoprim Diminishes B-Lymphocyte Immune Responses toPneumocystis murinaInfection in Healthy Mice

Feola

Garvy

2006

Clin Vaccine Immunol

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“…Sulphamethoxazole was the sulphonamide chosen to match trimethoprim on account of its pharmacokinetic properties; it is unfortunate that the active urinary level of this substance is so low, as little as 10 mg/l being present in the urine of some patients with impaired renal function (Rieder et al, 1974).…”

Section: Discussionmentioning

confidence: 99%

“…These three strains of E. coli were sensitive to the sulphamethoxazole (MIC less than 20 mg/I) and trimethoprim (MIC less than 1 mg/I), and each showed marked synergy with the mixture (ratio 20:1 w/w) in thymidine-free agar. The concentration of antibacterial substances was selected to represent active levels commonly found in urine Effect of thymidine on activity of trimethoprim and sulphamethoxazole after therapeutic doses (Rieder et al, 1974). Thus, the final concentration of both sulphamethoxazole and trimethoprim was 100 mg/l, either singly or in combination.…”

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confidence: 99%

Effect of thymidine on activity of trimethoprim and sulphamethoxazole.

Stokes¹,

Lacey²

1978

J Clin Pathol

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SUMMARY Thymidine at levels as low as 005 mg/l reduces the activities of sulphamethoxazole and trimethoprim and their combination in vitro. Using a biological assay procedure, levels of thymidine greater than this were interpreted as being present in urine. The addition of sulphamethoxazole and trimethoprim, singly or in combination, to urine obtained from patients with urinary tract infections showed that all the antibacterial effect towards sensitive organisms was due to the trimethoprim component. It is suggested that trimethoprim should replace the combination co-trimoxazole for the treatment of some lower urinary tract infections, and that laboratory media, if they are to resemble the clinical environment, should contain thymidine.

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“…Ratios of SMX/TMP in other tissues and fluids are different from the serum ratios, however, and may more closely approximate ratios yielding better synergism (6). SMX/ TMP ratios in urine have ranged from 1:4 to 3.5: 1 after single and repeated doses (3,13,22). TMP is probably concentrated by the prostate (15), and prostatic ratios in men may be very close to 1:1.…”

Section: Resultsmentioning

confidence: 99%

Sulfamethoxazole-trimethoprim synergism for Neisseria gonorrhoeae

Rein¹,

Elliott²,

Swenson³

et al. 1980

Antimicrob Agents Chemother

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Sulfamethoxazole and trimethoprim are synergistic against many bacteria in sulfamethoxazole/trimethoprim concentrations of 20:1, but single-dose therapy of gonorrhea with the combination is disappointing. We used agar dilution techniques to determine minimal inhibitory concentrations of sulfamethoxazole and trimethoprim for 168 gonococci isolated from men with acute urethritis in Atlanta, Ga. The geometric mean minimal inhibitory concentrations were 5.6 ,ug of sulfamethoxazole per ml and 24.3 ,tg of trimethoprim per ml, a ratio of 1:4. The concentration of sulfamethoxazole inhibiting 50% of gonococcal strains dropped only from 4.7 ,g/ml to 2.9 ,tg/ml with the addition of a 1/20 dilution of trimethoprim. We studied synergism with various ratios of sulfamethoxazole to trimethoprim against 20 random strains. A ratio of 1:1 was always synergistic and was the most synergistic ratio for 15 strains, whereas the 19:1 ratio was never the most synergistic. The 19:1 ratio failed to show synergism against seven strains, but showed antagonism at this ratio with five of these seven. The sulfamethoxazole/trimethoprim ratio of 19:1 usually achieved in serum after oral administration is minimally synergistic and is sometimes antagonistic for gonococci. Austin and colleagues tested 54 fresh isolates at two ratios of SMX/TMP and found that 1:3 was more synergistic than 20:1 (1). Stolz et al. found that a 1:1 ratio and a 1:20 ratio of SMX/TMP were more synergistic than the 20:1 ratio for 5 gonococcal isolates (23). Phillips and colleagues tested 30 strains and found that ratios of SMX/ TMP from 1:1 to 1:8 were generally more synergistic than ratios involving larger relative amounts of SMX (18). The ratio producing maximal synergy tended to be related to the ratio of the MICs of the individual drugs alone.We thought that the relatively low efficacy of single-dose SMX/TMP therapy for acute gonorrhea might result in part from a lack of synergism between the drugs. We determined the susceptibility to SMX and TMP of freshly isolated strains of N. gonorrhoeae and determined the synergistic effect of various combinations of the two drugs.

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Pharmacokinetics of the Antibacterial Combination Sulfamethoxazole plus Trimethoprim in Patients with Normal or Impaired Kidney Function

Cited by 52 publications

References 0 publications

Combination Exposure to Zidovudine plus Sulfamethoxazole-Trimethoprim Diminishes B-Lymphocyte Immune Responses toPneumocystis murinaInfection in Healthy Mice

Combination Exposure to Zidovudine plus Sulfamethoxazole-Trimethoprim Diminishes B-Lymphocyte Immune Responses toPneumocystis murinaInfection in Healthy Mice

Effect of thymidine on activity of trimethoprim and sulphamethoxazole.

Sulfamethoxazole-trimethoprim synergism for Neisseria gonorrhoeae

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