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Fractal Geometry-Based Decrease in Trimethoprim-Sulfamethoxazole Concentrations in Overweight and Obese People.

ABSTRACT: Trimethoprim-sulfamethoxazole (TMP-SMX) is one of the most widely drugs on earth. The World Health Organization recommends it as an essential basic drug for all healthcare systems. Dosing is inconsistently based on weight, assuming linear relationships. Given that obesity is now a global "pandemic" it is vital that we evaluate the effect of obesity on trimethoprim-sulfamethoxazole concentrations. We conducted a prospective clinical experiment based on optimized design strategies and artificial intelligence algorithms and found that weight and body mass index (BMI) had a profound effect on drug clearance and volume of distribution, and followed nonlinear fractal geometry-based relationships. The findings were confirmed by demonstrating decreased TMP-SMX peak and area under the concentration-time curves in overweight patients based on standard regression statistics. The nonlinear relationships can now be used to identify new TMP-SMX doses in overweight and obese patients for each of the infections caused by the >60 pathogens for which the drug is indicated.

SUBMITTER: Hall RG

PROVIDER: S-EPMC5193002 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Fractal Geometry-Based Decrease in Trimethoprim-Sulfamethoxazole Concentrations in Overweight and Obese People.

Hall R G RG Pasipanodya J G JG Meek C C Leff R D RD Swancutt M M Gumbo T T

CPT: pharmacometrics & systems pharmacology 20161121 12

Trimethoprim-sulfamethoxazole (TMP-SMX) is one of the most widely drugs on earth. The World Health Organization recommends it as an essential basic drug for all healthcare systems. Dosing is inconsistently based on weight, assuming linear relationships. Given that obesity is now a global "pandemic" it is vital that we evaluate the effect of obesity on trimethoprim-sulfamethoxazole concentrations. We conducted a prospective clinical experiment based on optimized design strategies and artificial i ...[more]

PMID: 27869362

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Project description:BackgroundU.S. emergency department visits for cutaneous abscess have increased with the emergence of methicillin-resistant Staphylococcus aureus (MRSA). The role of antibiotics for patients with a drained abscess is unclear.MethodsWe conducted a randomized trial at five U.S. emergency departments to determine whether trimethoprim-sulfamethoxazole (at doses of 320 mg and 1600 mg, respectively, twice daily, for 7 days) would be superior to placebo in outpatients older than 12 years of age who had an uncomplicated abscess that was being treated with drainage. The primary outcome was clinical cure of the abscess, assessed 7 to 14 days after the end of the treatment period.ResultsThe median age of the participants was 35 years (range, 14 to 73); 45.3% of the participants had wound cultures that were positive for MRSA. In the modified intention-to-treat population, clinical cure of the abscess occurred in 507 of 630 participants (80.5%) in the trimethoprim-sulfamethoxazole group versus 454 of 617 participants (73.6%) in the placebo group (difference, 6.9 percentage points; 95% confidence interval [CI], 2.1 to 11.7; P=0.005). In the per-protocol population, clinical cure occurred in 487 of 524 participants (92.9%) in the trimethoprim-sulfamethoxazole group versus 457 of 533 participants (85.7%) in the placebo group (difference, 7.2 percentage points; 95% CI, 3.2 to 11.2; P<0.001). Trimethoprim-sulfamethoxazole was superior to placebo with respect to most secondary outcomes in the per-protocol population, resulting in lower rates of subsequent surgical drainage procedures (3.4% vs. 8.6%; difference, -5.2 percentage points; 95% CI, -8.2 to -2.2), skin infections at new sites (3.1% vs. 10.3%; difference, -7.2 percentage points; 95% CI, -10.4 to -4.1), and infections in household members (1.7% vs. 4.1%; difference, -2.4 percentage points; 95% CI, -4.6 to -0.2) 7 to 14 days after the treatment period. Trimethoprim-sulfamethoxazole was associated with slightly more gastrointestinal side effects (mostly mild) than placebo. At 7 to 14 days after the treatment period, invasive infections had developed in 2 of 524 participants (0.4%) in the trimethoprim-sulfamethoxazole group and in 2 of 533 participants (0.4%) in the placebo group; at 42 to 56 days after the treatment period, an invasive infection had developed in 1 participant (0.2%) in the trimethoprim-sulfamethoxazole group.ConclusionsIn settings in which MRSA was prevalent, trimethoprim-sulfamethoxazole treatment resulted in a higher cure rate among patients with a drained cutaneous abscess than placebo. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00729937.).

Project description:BackgroundSkin and skin-structure infections are common in ambulatory settings. However, the efficacy of various antibiotic regimens in the era of community-acquired methicillin-resistant Staphylococcus aureus (MRSA) is unclear.MethodsWe enrolled outpatients with uncomplicated skin infections who had cellulitis, abscesses larger than 5 cm in diameter (smaller for younger children), or both. Patients were enrolled at four study sites. All abscesses underwent incision and drainage. Patients were randomly assigned in a 1:1 ratio to receive either clindamycin or trimethoprim-sulfamethoxazole (TMP-SMX) for 10 days. Patients and investigators were unaware of the treatment assignments and microbiologic test results. The primary outcome was clinical cure 7 to 10 days after the end of treatment.ResultsA total of 524 patients were enrolled (264 in the clindamycin group and 260 in the TMP-SMX group), including 155 children (29.6%). One hundred sixty patients (30.5%) had an abscess, 280 (53.4%) had cellulitis, and 82 (15.6%) had mixed infection, defined as at least one abscess lesion and one cellulitis lesion. S. aureus was isolated from the lesions of 217 patients (41.4%); the isolates in 167 (77.0%) of these patients were MRSA. The proportion of patients cured was similar in the two treatment groups in the intention-to-treat population (80.3% in the clindamycin group and 77.7% in the TMP-SMX group; difference, -2.6 percentage points; 95% confidence interval [CI], -10.2 to 4.9; P=0.52) and in the populations of patients who could be evaluated (466 patients; 89.5% in the clindamycin group and 88.2% in the TMP-SMX group; difference, -1.2 percentage points; 95% CI, -7.6 to 5.1; P=0.77). Cure rates did not differ significantly between the two treatments in the subgroups of children, adults, and patients with abscess versus cellulitis. The proportion of patients with adverse events was similar in the two groups.ConclusionsWe found no significant difference between clindamycin and TMP-SMX, with respect to either efficacy or side-effect profile, for the treatment of uncomplicated skin infections, including both cellulitis and abscesses. (Funded by the National Institute of Allergy and Infectious Diseases and the National Center for Advancing Translational Sciences, National Institutes of Health; ClinicalTrials.gov number, NCT00730028.).

Project description:BackgroundMelioidosis, an infectious disease caused by the Gram-negative bacillus Burkholderia pseudomallei, is difficult to cure. Antimicrobial treatment comprises intravenous drugs for at least 10 days, followed by oral drugs for at least 12 weeks. The standard oral regimen based on trial evidence is trimethoprim-sulfamethoxaxole (TMP-SMX) plus doxycycline. This regimen is used in Thailand but is associated with side-effects and poor adherence by patients, and TMP-SMX alone is recommended in Australia. We compared the efficacy and side-effects of TMP-SMX with TMP-SMX plus doxycycline for the oral phase of melioidosis treatment.MethodsFor this multi-centre, double-blind, non-inferiority, randomised placebo-controlled trial, we enrolled patients (aged ≥15 years) from five centres in northeast Thailand with culture-confirmed melioidosis who had received a course of parenteral antimicrobial drugs. Using a computer-generated sequence, we randomly assigned patients to receive TMP-SMX plus placebo or TMP-SMX plus doxycycline for 20 weeks (1:1; block size of ten, stratified by study site). We followed patients up every 4 months for 1 year and annually thereafter to the end of the study. The primary endpoint was culture-confirmed recurrent melioidosis, and the non-inferiority margin was a hazard ratio (HR) of 1.7. This study is registered with www.controlled-trials.com, number ISRCTN86140460.FindingsWe enrolled and randomly assigned 626 patients: 311 to TMP-SMX plus placebo and 315 to TMP-SMX plus doxycycline. 16 patients (5%) in the TMP-SMX plus placebo group and 21 patients (7%) in the TMP-SMX plus doxycycline group developed culture-confirmed recurrent melioidosis (HR 0.81; 95% CI 0.42-1.55). The criterion for non-inferiority was met (p=0.01). Adverse drug reactions were less common in the TMP-SMX plus placebo group than in the TMP-SMX plus doxycycline group (122 [39%] vs 167 [53%]).InterpretationOur findings suggest that TMP-SMX is not inferior to TMP-SMX plus doxycycline for the oral phase of melioidosis treatment, and is preferable on the basis of safety and tolerance by patients.FundingThailand Research Fund, the Melioidosis Research Center, the Center of Excellence in Specific Health Problems in Greater Mekong Sub-region cluster, and the Wellcome Trust.

Project description:Trimethoprim (TMP)-sulfamethoxazole (SMX) is used to treat various types of infections, including community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) and Pneumocystis jirovecii infections in children. Pharmacokinetic (PK) data for infants and children are limited, and the optimal dosing is not known. We performed a multicenter, prospective PK study of TMP-SMX in infants and children. Separate population PK models were developed for TMP and SMX administered by the enteral route using nonlinear mixed-effects modeling. Optimal dosing was determined on the basis of the matching adult TMP exposure and attainment of the surrogate pharmacodynamic (PD) target for efficacy, a free TMP concentration above the MIC over 50% of the dosing interval. Data for a total of 153 subjects (240 samples for PK analysis) with a median postnatal age of 8 years (range, 0.1 to 20 years) contributed to the analysis for both drugs. A one-compartment model with first-order absorption and elimination characterized the TMP and SMX PK data well. Weight was included in the base model for clearance (CL/F) and volume of distribution (V/F). Both TMP and SMX CL/F increased with age. In addition, TMP and SMX CL/F were inversely related to the serum creatinine and albumin concentrations, respectively. The exposure achieved in children after oral administration of TMP-SMX at 8/40 mg/kg of body weight/day divided into administration every 12 h matched the exposure achieved in adults after administration of TMP-SMX at 320/1,600 mg/day divided into administration every 12 h and achieved the PD target for bacteria with an MIC of 0.5 mg/liter in >90% of infants and children. The exposure achieved in children after oral administration of TMP-SMX at 12/60 and 15/75 mg/kg/day divided into administration every 12 h matched the exposure achieved in adults after administration of TMP-SMX at 640/3,200 mg/day divided into administration every 12 h in subjects 6 to <21 years and 0 to <6 years of age, respectively, and was optimal for bacteria with an MIC of up to 1 mg/liter.

Dataset Information

Fractal Geometry-Based Decrease in Trimethoprim-Sulfamethoxazole Concentrations in Overweight and Obese People.

Publications

Fractal Geometry-Based Decrease in Trimethoprim-Sulfamethoxazole Concentrations in Overweight and Obese People.

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