trimethoprim--sulfamethoxazole-drug-combination and Body-Weight

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.

Topics: Adult; Aged; Anti-Bacterial Agents; Artificial Intelligence; Body Weight; Drug Dosage Calculations; Female; Fractals; Humans; Male; Metabolic Clearance Rate; Middle Aged; Obesity; Overweight; Prospective Studies; Trimethoprim, Sulfamethoxazole Drug Combination; Young Adult

The World Health Organization guidelines recommend cotrimoxazole prophylactic treatment (CPT) for all HIV-exposed infants from age 6 weeks to the cessation of breastfeeding and the exclusion of HIV infection. There are limited data on the effects of CPT among this population of infants. We examined the effects of CPT on adverse health outcomes among HIV-exposed infants during the first 36 weeks of life using data from the Breastfeeding, Antiretrovirals and Nutrition study, a large clinical trial of antiretroviral drugs given to the mother or infant for the prevention of HIV transmission during breastfeeding.. For the analysis, we assigned a status of CPT-exposed to infants who were participating in the study after the CPT program started. We estimated unadjusted and adjusted hazard ratios for the effect of CPT status on time to incident malaria, severe illness or death, anemia, and weight-for-age Z score < -2.0. Participation in the study was limited to focus exclusively on HIV-exposed, uninfected infants.. The hazard ratio for the effect of CPT on incident malaria was 0.35 (95% confidence interval: 0.21, 0.57) during the first 10 weeks of CPT exposure and 0.93 (95% confidence interval: 0.67, 1.29) for the remaining 20 weeks. CPT was not associated with the other outcomes examined.. CPT offered temporary protection against malaria among HIV-exposed, uninfected infants. However, CPT offered no protection against anemia, low weight for age or the collapsed outcome of severe illness or death.

Topics: Anemia; Anti-Retroviral Agents; Antibiotic Prophylaxis; Antimalarials; Body Weight; Breast Feeding; Chi-Square Distribution; Female; HIV Infections; Humans; Infant; Infant, Newborn; Kaplan-Meier Estimate; Malaria; Mothers; Statistics, Nonparametric; Trimethoprim, Sulfamethoxazole Drug Combination

The impact of cotrimoxazole (CTX) on growth and/or anemia was investigated in 541 human immunodeficiency virus-infected, antiretroviral therapy-naive Zambian children enrolled in the Children with HIV Antibiotic Prophylaxis trial. Compared with children randomized to receive placebo, children randomized to receive CTX had slower decreases in weight-for-age (P=.04) and height-for-age (P=.01), and greater increase in hemoglobin level (P=.01). These findings argue for expanded early CTX use.

Topics: Adolescent; Anemia; Antimalarials; Body Height; Body Weight; Chemoprevention; Child; Child Development; Child, Preschool; Female; HIV Infections; Humans; Infant; Malaria; Male; Placebos; Trimethoprim, Sulfamethoxazole Drug Combination; Zambia

Topics: Anti-Infective Agents, Urinary; Body Weight; Child; Child, Preschool; Drug Combinations; Female; Growth; Humans; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination; Urinary Tract Infections

The growth benefits of cotrimoxazole during early antiretroviral therapy (ART) are not well characterized.. Individuals enrolled in the Therapeutics Research, Education, and AIDS Training in Asia Pediatric HIV Observational Database were included if they started ART at ages 1 month-14 years and had both height and weight measurements available at ART initiation (baseline). Generalized estimating equations were used to identify factors associated with change in height-for-age z-score (HAZ), follow-up HAZ ≥ -2, change in weight-for-age z-score (WAZ), and follow-up WAZ ≥ -2.. A total of 3217 children were eligible for analysis. The adjusted mean change in HAZ among cotrimoxazole and non-cotrimoxazole users did not differ significantly over the first 24 months of ART. In children who were stunted (HAZ < -2) at baseline, cotrimoxazole use was not associated with a follow-up HAZ ≥ -2. The adjusted mean change in WAZ among children with a baseline CD4 percentage (CD4%) >25% became significantly different between cotrimoxazole and non-cotrimoxazole users after 6 months of ART and remained significant after 24 months (overall P < .01). Similar changes in WAZ were observed in those with a baseline CD4% between 10% and 24% (overall P < .01). Cotrimoxazole use was not associated with a significant difference in follow-up WAZ in children with a baseline CD4% <10%. In those underweight (WAZ < -2) at baseline, cotrimoxazole use was associated with a follow-up WAZ ≥ -2 (adjusted odds ratio, 1.70 vs not using cotrimoxazole [95% confidence interval, 1.28-2.25], P < .01). This association was driven by children with a baseline CD4% ≥10%.. Cotrimoxazole use is associated with benefits to WAZ but not HAZ during early ART in Asian children.

Topics: Anti-Bacterial Agents; Anti-HIV Agents; Antibiotic Prophylaxis; Asia; Body Height; Body Weight; Child; Child Development; Child, Preschool; Drug Therapy, Combination; Female; HIV Infections; Humans; Infant; Male; Trimethoprim, Sulfamethoxazole Drug Combination

Two patients, a girl and a boy, both aged 8.5 years, presented with serious side effects caused by ceftriaxone and co-trimoxazole, respectively. The first patientwas treated with ceftriaxone (100 mg/kg/day with a body weight of 35.6 kg) on suspicion of a neuroborreliosis, but developed an acute cholecystitis with cholelithiasis 3 weeks after the antibiotic had been withdrawn. He underwent a laparoscopic cholecystectomy. Ceftriaxone binds calcium in the biliary tract, forming biliary sludge or stones. The second patient developed thrombocytopenia during treatment with co-trimoxazole (58 mg/kg/day with a body weight of 25.4 kg) because of a urinary-tract infection. After discontinuation of the co-trimoxazole the thrombocytopenia resolved spontaneously. The pathophysiological mechanism involved may be either a direct toxic effect of trimethoprim or an immune-mediated reaction to sulfamethoxazole. According to current guidelines, the dosage of the drug was too high in both cases. It is important to ensure a correct dosage in children, since side effects are potentially dose-related.

Topics: Anti-Bacterial Agents; Body Weight; Ceftriaxone; Child; Cholelithiasis; Dose-Response Relationship, Drug; Female; Humans; Male; Thrombocytopenia; Trimethoprim, Sulfamethoxazole Drug Combination; Urinary Tract Infections

Trimethoprim-sulfamethoxazole (TMP-SMX) medication in the feed or water is commonly administered to immunocompro mised mice to prevent the occurrence of Pneumocystis murina (formerly P. carinii) pneumonia. Therapeutic doses of SMX can cause decreased total and free thyroxine (T4) levels in dogs and thyroid hypertrophy and hyperplasia in mice, rats, and dogs. Our primary objective was to determine whether SMX at doses present in commercially available rodent TMP-SMX feed would pro duce hypothyroidism in mice. Plasma T4 levels were determined prior to and after placement of Brand A TMP-SMX feed (daily SMX dose, 240 mg/kg), Brand B TMP-SMX feed (daily SMX dose, 2400 mg/kg), and their respective controls (doses calculated for a 25-g mouse according to vendor's information). T4 levels in the mice fed Brand B TMP-SMX feed were significantly decreased by 2 wk after feed placement. Levels of thyroid stimulating hormone in male and female mice given Brand B TMP-SMX feed were significantly elevated compared with those of control groups at 6 wk after feed placement, when only these mice showed evidence of thyroid hypertrophy and hyperplasia. No significant change in T4 levels occurred over the course of 11 wk in mice given the Brand A TMP-SMX chow or either control feed. In light of the significant clinical hypothyroidism that occurred in our mice while receiving Brand B TMP-SMX diet, we recommend SMX levels more similar to that of Brand A to avoid such unwanted effects which could confound research data.

Topics: Animal Feed; Animals; Body Weight; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Female; Fertility; Hypothyroidism; Male; Mice; Mice, Inbred C57BL; Rodent Diseases; Thyroid Gland; Thyrotropin; Thyroxine; Trimethoprim, Sulfamethoxazole Drug Combination

Benanomicin A (BNM-A) has antimycotic activities via binding to mannan in the cell walls of fungi. Anti-Pneumocystis carinii activity of the agent was examined in the P. carinii-infected BALB/c nu/nu female mouse model because P. carinii also possesses mannan in the membranes. The infected mice were treated with intraperitoneal injections of six doses of BNM-A (1, 2.5, 5, 10, 30, and 100 mg/kg of body weight), 4 mg of pentamidine isethionate per kg, 100 mg of sulfamethoxazole per kg combined with 20 mg of trimethoprim per kg (co-trimoxazole), or saline for 21 days. Each dosage group consisted of 10 mice. During treatment, five mice in the control group (saline) died, whereas 8 to 10 mice in all treatment groups survived. Almost the same efficacies were obtained for the groups treated with 5 mg or more and 10 mg or more of BNM-A per kg regarding the weight and number, respectively, of cysts found in the lungs as were obtained for the groups treated with pentamidine isethionate and co-trimoxazole. Overall, a dose of 10 mg of BNM-A per kg was effective against P. carinii pneumonia infection in the mice. Thus, BNM-A is a good candidate for a novel treatment for P. carinii pneumonia as a compound with a new mechanism of action against P. carinii.

Topics: Animals; Anthracyclines; Antibiotics, Antineoplastic; Antifungal Agents; Body Weight; Female; Lung; Mice; Mice, Inbred BALB C; Mice, Nude; Organ Size; Pentamidine; Pneumonia, Pneumocystis; Trimethoprim, Sulfamethoxazole Drug Combination

The disposition of 12 mg of trimethoprim and 60 mg of sulfamethoxazole per kg of body weight in six healthy male volunteers is described. The daily dose was evenly divided and administered orally every 6 h for 13 consecutive doses. Individual drug components were assayed by high-performance liquid chromatography. Steady-state concentrations in serum for trimethoprim and sulfamethoxazole were within the purported therapeutic ranges for treating Pneumocystis carinii pneumonia. Co-trimoxazole was well tolerated, and no subject withdrew from the study because of toxicity. Comparison of the pharmacokinetic parameters in this study with those of our previous findings indicates that the elimination of trimethoprim-sulfamethoxazole follows a first-order process within the dose ranges assessed. Administration of 15- to 20-mg/kg trimethoprim and 75- to 100-mg/kg sulfamethoxazole in four evenly divided doses for the first 24 h followed by 12 and 60 mg/kg/day, respectively, for the remainder of therapy rapidly attains concentrations in serum within the proposed P. carinii pneumonia therapeutic range. Clinical trials are indicated to evaluate this dosing scheme, which may decrease exposure to potentially excessive concentrations of trimethoprim and sulfamethoxazole.

Topics: Adult; Body Weight; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Male; Sulfamethoxazole; Trimethoprim, Sulfamethoxazole Drug Combination

Low-dose trimethoprim-sulfamethoxazole (TMP-SMX) alone was found to be as effective as low-dose TMP-SMX plus zidovudine and standard-dose TMP-SMX alone in preventing and treating Pneumocystis carinii pneumonia (PCP) in an immunosuppressed-rat model. Zidovudine alone had no preventive or curative effect on PCP. We conclude that the initially reported reduced incidence of PCP in human immunodeficiency virus-infected patients treated with zidovudine alone is not due to anti-P. carinii activity of zidovudine. Furthermore, the clinical efficacy of low-dose TMP-SMX for the prevention and treatment of PCP should be further investigated.

Topics: Animals; Body Weight; Drug Evaluation, Preclinical; Drug Therapy, Combination; Immunosuppression Therapy; Male; Mice; Pneumonia, Pneumocystis; Rats; Rats, Wistar; Trimethoprim, Sulfamethoxazole Drug Combination; Zidovudine

The rate of hydrolysis of three cysteine-type proteinase substrates, N-benzyloxycarbonyl-Arg-Arg-4-methyl-7-coumarylamide (AMC) (cathepsin B), Arg-AMC (cathepsin H), and N-benzyloxycarbonyl-Phe-Arg-AMC (cathepsin L), were determined in rat lung throughout the time course of the induction of Pneumocystis carinii infection by immunosuppression. Cathepsin B-like and cathepsin L-like activities fell below control values initially, but from week 8 of the immunosuppressive treatment significant increases above the control were noted. Cathepsin H-like activity was greater than control levels from week 3, and by week 12 it was 7,600% of the mean control value. When compared with the relative degree of infection, as assessed from the number of cysts present in lung impression smears, cathepsin B-like and cathepsin L-like activities were significantly increased only at heavy parasite burdens while cathepsin H-like activity displayed a close correlation with parasite number (r = 0.884; P less than 0.001). Activity was detected in lysates of purified P. carinii with all three substrates. Treatment of heavily infected animals with co-trimoxazole cleared the lungs of P. carinii, and this was accompanied by a marked reduction in proteinase activity, in particular, cathepsin H-like activity, which fell from 108- to 3-fold the mean control value following drug treatment. Analysis of cathepsin H isozyme patterns by fluorography following isoelectric focusing revealed differences between treated and control lung samples. In the immunosuppressed group, there was a time-dependent increase in the intensity of some of the bands observed in the controls and an appearance of several novel bands which corresponded to bands observed in lysates of P. carinii. It is likely, therefore, that the increased proteinase activity observed in the treated group is due, at least in part, to isozymes from P. carinii; consequently, cathepsin H-like activity might be of use diagnostically in the identification of P. carinii infection and in the estimation of parasite burden.

Topics: Animals; Body Weight; Cathepsin B; Cathepsin H; Cathepsin L; Cathepsins; Cysteine Endopeptidases; Endopeptidases; Isoelectric Focusing; Leucine; Lung; Male; Pneumocystis; Pneumonia, Pneumocystis; Rats; Rats, Inbred Strains; Time Factors; Trimethoprim, Sulfamethoxazole Drug Combination

Several radiological studies have suggested that pyelonephritis in infancy and childhood may result in kidney growth retardation without renal scarring. In the present study, we induced ascending pyelonephritis in 20-day-old rats with intravesical infusion of E. coli. Four days after infusion, E. coli was cultured from all renal cortex. The rats were either left untreated (PNu) or were treated with trimethoprim-sulfa (PNt). The rats were investigated one month after infection and compared with an age-matched control group (C). Seventy-nine percent of the PNu rats had recovered spontaneously from infection. Body weight was the same in all groups. In PNu rats, kidney weight (KW), kidney area (KA) and glomerular filtration rate (GFR) were significantly decreased. KW, KA and GFR were similar in PNt and C rats. The numbers of filtering nephrons were not reduced by the infection. The total cortical DNA content (index of cell number) was significantly lower in PNu (5.30 +/- 0.32 mg) and PNt (6.62 +/- 0.44 mg) than in C rats (8.48 +/- 0.49 mg). The cortical DNA content was significantly lower in PNu than in PNt rats. The cortical protein/DNA ratio was significantly higher in PNu rats than in C rats. The protein/DNA ratio was similar in PNt and PNu rats. The increase in protein/DNA ratio was interpreted as a sign of cell hypertrophy. The inflammatory process as such did not increase the protein/DNA ratio. The kidneys were also examined for structural lesions. Signs of scarring, inflammation and cell necrosis were almost absent in all groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aging; Animals; Body Weight; DNA; Drug Combinations; Escherichia coli Infections; Female; Glomerular Filtration Rate; Kidney; Organ Size; Proteins; Pyelonephritis; Rats; Rats, Inbred Strains; Reference Values; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination; Urinary Bladder

Topics: Acute Kidney Injury; Adolescent; Body Weight; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Combinations; Humans; Infant; Kidney Failure, Chronic; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Co-trimoxazole is an effective antibacterial agent for the prophylaxis of urinary tract infection. Because experimental evidence raises the possibility that high-dose cotrimoxazole might interfere with normal somatic growth, the longitudinal growth and growth velocities were analysed in 114 girls receiving long-term, low-dose prophylactic cotrimoxazole. They were aged 2-12 years at the start of prophylaxis which was given in a daily dose of approximately 10 mg sulphamethoxazole (SMX) and 2 mg trimethoprim (TMP)/kg body weight for at least 6 months and for up to 6 years. There was no significant variation from normal in height or weight attained or in growth velocity overall in 114 girls, 51 of whom had vesico-ureteric reflux (VUR). No difference was found in growth velocity when periods of 6 months on or off prophylactic therapy were compared in 53 girls. Growth did not vary between cohorts of girls receiving co-trimoxazole prophylaxis for 2, 3 or 4 years and growth proceeded normally in the 51 girls with VU reflux. We have not found evidence that long-term, low-dose cotrimoxazole prophylaxis has any adverse effect upon somatic growth in girls with a previous urinary infection with or without vesico-ureteric reflux and who are otherwise healthy.

Topics: Body Height; Body Weight; Child; Child, Preschool; Drug Combinations; Female; Growth; Humans; Sulfamethoxazole; Time Factors; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination; Urinary Tract Infections; Vesico-Ureteral Reflux