Pharmacokinetic modeling of sulfamethoxazole-trimethoprim and sulfadiazine-trimethoprim combinations in broilers.

Sulfonamides (S) are old bacteriostatic antibiotics which are widely prescribed in combination with trimethoprim (TMP) for the treatment of various diseases in food-producing animals such as poultry. Nowadays, the 1:5 dose ratio of TMP/S used in broilers is a direct transposition of the ratio determined in Human decades ago for TMP/sulfamethoxazole (SMX), aiming to obtain a supposed synergistic plasma concentration ratio of 1:19. However, major pharmacokinetics (PK) differences exist according to the sulfonamide used in the combination. Here, we generated new PK data in broilers after a cross-over design with IV and the oral administration of 2 major sulfonamides, sulfadiazine (SDZ) and SMX, in combination with TMP, and analyzed the data via a population pharmacokinetic (popPK) modeling approach. Results showed that TMP has a greater plasma to tissue distribution than both sulfonamides with a higher volume of distribution (0.51 L/kg for SDZ, 0.62 L/kg for SMX and 3.14 L/kg for TMP). SMX has the highest elimination half-life (2.83 h) followed by SDZ and TMP (2.01 h and 1.49 h, respectively). The oral bioavailability of the 3 molecules was approximately 100%. Bodyweight could explain some of the inter-individual variability in the volume of distribution of SDZ and SMX and the clearance of SDZ and TMP, as heavier broilers have higher typical values. Monte Carlo simulations of a large virtual broiler population (n = 1,000) showed that the targeted plasma ratio of TMP:S of 1:19 was rarely or never reached at the individual level for both combinations at the marketed doses and greatly varies over time and between individuals, questioning the relevance of the 1:5 dose ratio for current formulations of TMP/S.

Development and Evaluation of a Virtual Population of Children with Obesity for Physiologically Based Pharmacokinetic Modeling.

BACKGROUND AND OBJECTIVE: While one in five children in the USA are now obese, and more than three-quarters receive at least one drug during childhood, there is limited dosing guidance for this vulnerable patient population. Physiologically based pharmacokinetic modeling can bridge the gap in the understanding of how pharmacokinetics, including drug distribution and clearance, changes with obesity by incorporating known obesity-related physiological changes in children. The objective of this study was to develop a virtual population of children with obesity to enable physiologically based pharmacokinetic modeling, then use the novel virtual population in conjunction with previously developed models of clindamycin and trimethoprim/sulfamethoxazole to better understand dosing of these drugs in children with obesity. METHODS: To enable physiologically based pharmacokinetic modeling, a virtual population of children with obesity was developed using national survey, electronic health record, and clinical trial data, as well as data extracted from the literature. The virtual population accounts for key obesity-related changes in physiology relevant to pharmacokinetics, including increased body size, body composition, organ size and blood flow, plasma protein concentrations, and glomerular filtration rate. The virtual population was then used to predict the pharmacokinetics of clindamycin and trimethoprim/sulfamethoxazole in children with obesity using previously developed physiologically based pharmacokinetic models. RESULTS: Model simulations predicted observed concentrations well, with an overall average fold error of 1.09, 1.24, and 1.53 for clindamycin, trimethoprim, and sulfamethoxazole, respectively. Relative to children without obesity, children with obesity experienced decreased clindamycin and trimethoprim/sulfamethoxazole weight-normalized clearance and volume of distribution, and higher absolute doses under recommended pediatric weight-based dosing regimens. CONCLUSIONS: Model simulations support current recommended weight-based dosing in children with obesity for clindamycin and trimethoprim/sulfamethoxazole, as they met target exposure despite these changes in clearance and volume of distribution.

External Evaluation of Two Pediatric Population Pharmacokinetics Models of Oral Trimethoprim and Sulfamethoxazole.

The antibiotic combination trimethoprim (TMP)-sulfamethoxazole (SMX) has a broad spectrum of activity and is used for the treatment of numerous infections, but pediatric pharmacokinetic (PK) data are limited. We previously published population PK (popPK) models of oral TMP-SMX in pediatric patients based on sparse opportunistically collected data (POPS study) (J. Autmizguine, C. Melloni, C. P. Hornik, S. Dallefeld, et al., Antimicrob Agents Chemother 62:e01813-17, 2017, https://doi.org/10.1128/AAC.01813-17). We performed a separate PK study of oral TMP-SMX in infants and children with more-traditional PK sample collection and independently developed new popPK models of TMP-SMX using this external data set. The POPS data set and the external data set were each used to evaluate both popPK models. The external TMP model had a model and error structure identical to those of the POPS TMP model, with typical values for PK parameters within 20%. The external SMX model did not identify the covariates in the POPS SMX model as significant. The external popPK models predicted higher exposures to TMP (median overprediction of 0.13 mg/liter for the POPS data set and 0.061 mg/liter for the external data set) and SMX (median overprediction of 1.7 mg/liter and 0.90 mg/liter) than the POPS TMP (median underprediction of 0.016 mg/liter and 0.39 mg/liter) and SMX (median underprediction of 1.2 mg/liter and 14 mg/liter) models. Nonetheless, both models supported TMP-SMX dose increases in infants and young children for resistant pathogens with a MIC of 1 mg/liter, although the required dose increase based on the external model was lower. (The POPS and external studies have been registered at ClinicalTrials.gov under registration no. NCT01431326 and NCT02475876, respectively.).

Physiologically Based Pharmacokinetic Modeling for Trimethoprim and Sulfamethoxazole in Children.

OBJECTIVE: The aims of this study were to (1) determine whether opportunistically collected data can be used to develop physiologically based pharmacokinetic (PBPK) models in pediatric patients; and (2) characterize age-related maturational changes in drug disposition for the renally eliminated and hepatically metabolized antibiotic trimethoprim (TMP)-sulfamethoxazole (SMX). METHODS: We developed separate population PBPK models for TMP and SMX in children after oral administration of the combined TMP-SMX product and used sparse and opportunistically collected plasma concentration samples to validate our pediatric model. We evaluated predictability of the pediatric PBPK model based on the number of observed pediatric data out of the 90% prediction interval. We performed dosing simulations to target organ and tissue (skin) concentrations greater than the methicillin-resistant Staphylococcus aureus (MRSA) minimum inhibitory concentration (TMP 2 mg/L; SMX 9.5 mg/L) for at least 50% of the dosing interval. RESULTS: We found 67-87% and 71-91% of the observed data for TMP and SMX, respectively, were captured within the 90% prediction interval across five age groups, suggesting adequate fit of our model. Our model-rederived optimal dosing of TMP at the target tissue was in the range of recommended dosing for TMP-SMX in children in all age groups by current guidelines for the treatment of MRSA. CONCLUSION: We successfully developed a pediatric PBPK model of the combination antibiotic TMP-SMX using sparse and opportunistic pediatric pharmacokinetic samples. This novel and efficient approach has the potential to expand the use of PBPK modeling in pediatric drug development.

Drawbacks of the use of cotrimoxazole in foreign-body infections.

INTRODUCTION: The anti-staphylococcal efficacy of cotrimoxazole in the setting of difficult-to-treat infections seems to be compromised by large amounts of pus and devitalized tissue, and, therefore, high levels of thymidine. Our objective was to evaluate the activity of cotrimoxazole against a staphylococcal foreign-body infection experimental model, which also yields significant quantities of thymidine. MATERIAL AND METHODS: We used a rat tissue-cage model of infection (with high inherent thymidine levels) caused by a strain of methicillin-susceptible Staphylococcus aureus (MSSA; ATCC 29213). MIC values were determined (microdilution method) and compared in the presence or absence of tissue-cage fluid samples. RESULTS: The inefficacy of cotrimoxazole was found to be similar to that of the control group. The MIC of cotrimoxazole was 4-8 fold higher in the presence of rat tissue-cage fluid. CONCLUSIONS: The inefficacy of cotrimoxazole in our foreign-body infection model by MSSA, and the probable negative impact of the presence of thymidine on its efficacy, challenge the use of this drug in acute phases of foreign-body infections. It should be reserved as an alternative treatment when the infection is more controlled.

Population Pharmacokinetics of Trimethoprim-Sulfamethoxazole in Infants and Children.

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.

Suboptimal cotrimoxazole prophylactic concentrations in HIV-infected children according to the WHO guidelines.

AIMS: A clinical study was conduct in HIV-infected children to evaluate the prophylactic doses of cotrimoxazole [sulfamethoxazole (SMX) and trimethoprim (TMP)] advised by the WHO. METHODS: Children received lopinavir-based antiretroviral therapy with cotrimoxazole prophylaxis (200 mg of SMX/40 mg of TMP once daily). A nonlinear mixed effects modelling approach was used to analyse plasma concentrations. Factors that could impact the pharmacokinetic profile were investigated. The model was subsequently used to simulate individual exposure and evaluate different administration schemes. RESULTS: The cohort comprised 136 children [average age: 1.9 years (range: [0.7-4]), average weight: 9.5 kg (range: [6-16.3])]. A dose per kg was justified by the significant influence of implementing an allometrically scaled body size covariate on SMX and TMP pharmacokinetics. SMX and TPM clearance were estimated at 0.49 l h-1 /9.5 kg and 3.06 l h-1 /9.5 kg, respectively. The simulated exposures obtained after administration of oral dosing recommended by the WHO for children from 10 to 15 kg were significantly lower than in adults for SMX and TMP. This could induce a reduction of effectiveness of cotrimoxazole. Simulations show that regimens of 30 mg kg-1 of SMX and 6 mg kg-1 of TMP in the 5-10 kg group and 25 mg kg-1 of SMX and 5 mg kg-1 of TMP in the 10-15 kg group are more suitable doses. CONCLUSIONS: In this context of high prevalence of opportunistic infections, a lower exposure to cotrimoxazole in children than adults was noted. To achieve comparable exposure to adults, a dosing scheme per kg was proposed.

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

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.

Population Pharmacokinetics and Pharmacodynamics of Lumefantrine in Young Ugandan Children Treated With Artemether-Lumefantrine for Uncomplicated Malaria.

BACKGROUND: The pharmacokinetics and pharmacodynamics of lumefantrine, a component of the most widely used treatment for malaria, artemether-lumefantrine, has not been adequately characterized in young children. METHODS: Capillary whole-blood lumefantrine concentration and treatment outcomes were determined in 105 Ugandan children, ages 6 months to 2 years, who were treated for 249 episodes of Plasmodium falciparum malaria with artemether-lumefantrine. RESULTS: Population pharmacokinetics for lumefantrine used a 2-compartment open model with first-order absorption. Age had a significant positive correlation with bioavailability in a model that included allometric scaling. Children not receiving trimethoprim-sulfamethoxazole with capillary whole blood concentrations <200 ng/mL had a 3-fold higher hazard of 28-day recurrent parasitemia, compared with those with concentrations >200 ng/mL (P = .0007). However, for children receiving trimethoprim-sulfamethoxazole, the risk of recurrent parasitemia did not differ significantly on the basis of this threshold. Day 3 concentrations were a stronger predictor of 28-day recurrence than day 7 concentrations. CONCLUSIONS: We demonstrate that age, in addition to weight, is a determinant of lumefantrine exposure, and in the absence of trimethoprim-sulfamethoxazole, lumefantrine exposure is a determinant of recurrent parasitemia. Exposure levels in children aged 6 months to 2 years was generally lower than levels published for older children and adults. Further refinement of artemether-lumefantrine dosing to improve exposure in infants and very young children may be warranted.

Pharmacokinetics and pharmacodynamics of sulfamethoxazole and trimethoprim in swimming crabs (Portunus trituberculatus) and in vitro antibacterial activity against Vibrio: PK/PD of SMZ-TMP in crabs and antibacterial activity against Vibrio.

Serious bacterial pathogens have recently become a major cause of massive mortality in swimming crabs (Portunus trituberculatus). In this study, the antibacterial activity against Vibrio and the pharmacokinetics (PK) of sulfamethoxazole (SMZ)-trimethoprim (TMP) in crabs were estimated to explore the pharmacokinetics/pharmacodynamics (PK/PD) properties of the SMZ-TMP combination. The in vitro bacteriostatic activity and the anti-Vibrio infection activity of the SMZ-TMP combination at various ratios in crabs were studied. A degree of synergism was observed in the SMZ-TMP combination at ratios ranging from 50:1 to 1:5. The results showed that the MIC50 and MIC90 values for different SMZ-TMP combinations were in the ranges of 0.62-5 and 0.62-10µg/mL, respectively. The distribution of the MIC values of the SMZ-TMP combination at ratios of 1:1 and 5:1 were 0.31-5 and 0.31-10µg/mL, respectively. Crabs were then fed the SMZ-TMP combination (at ratios of 5:1 and 1:1) six successive times and then challenged with Vibrio parahaemolyticus at 1×10(5), 1×10(6), and 5×10(6) colony forming units (cfu) per crab. The results showed that the number of surviving crabs administered SMZ-TMP at a ratio of 1:1 was greater than that of the crabs given SMZ-TMP at a ratio of 5:1. In addition, the tissue distribution and absorption of SMZ-TMP (ratios of 5:1 and 1:1) in crabs were studied through high-performance liquid chromatography (HPLC). In the crabs fed SMZ-TMP at a ratio of 5:1, the CmaxSMZ/TMP values in the hemolymph, hepatopancreas, muscle and gill were 104:1. 0.57:1, 19:1 and 6:1, respectively. In contrast, the corresponding CmaxSMZ/TMP values in these tissues in the crabs fed SMZ-TMP at a ratio of 1:1 were 34:1, 0.14:1, 4:1 and 3:1, respectively. The results showed that TMP was better absorbed and eliminated in the crabs fed SMZ-TMP at a ratio of 1:1 than in the crabs fed this combination at a ratio of 5:1. In addition, TMP was absorbed and eliminated more rapidly in the hepatopancreas than in the gill, muscle and hemolymph. The distribution volume of TMP in the hepatopancreas exceeded that of SMZ observed in the experiments. The results indicated that the PK/PD effect of the SMZ-TMP at a ratio of 1:1 was greater than that of the combination at a ratio of 5:1. Our study suggests that a SMZ-TMP ratio of 1:1 may be used to control bacterial disease in aquatic animals.

Evaluation of Trimethoprim/Sulfamethoxazole (SXT), Minocycline, Tigecycline, Moxifloxacin, and Ceftazidime Alone and in Combinations for SXT-Susceptible and SXT-Resistant Stenotrophomonas maltophilia by In Vitro Time-Kill Experiments.

BACKGROUND: The optimal therapy for infections caused by Stenotrophomonas maltophilia (S. maltophilia) has not yet been established. The objective of our study was to evaluate the efficacy of trimethoprim/sulfamethoxazole (SXT), minocycline, tigecycline, moxifloxacin, levofloxacin, ticarcillin-clavulanate, polymyxin E, chloramphenicol, and ceftazidime against clinical isolated S. maltophilia strains by susceptibility testing and carried out time-kill experiments in potential antimicrobials. METHODS: The agar dilution method was used to test susceptibility of nine candidate antimicrobials, and time-killing experiments were carried out to evaluate the efficacy of SXT, minocycline, tigecycline, moxifloxacin, levofloxacin, and ceftazidime both alone and in combinations at clinically relevant antimicrobial concentrations. RESULTS: The susceptibility to SXT, minocycline, tigecycline, moxifloxacin, levofloxacin, ticarcillin-clavulanate, chloramphenicol, polymyxin E, and ceftazidime were 93.8%, 95.0%, 83.8%, 80.0%, 76.3%, 76.3%, 37.5%, 22.5%, and 20.0% against 80 clinical consecutively isolated strains, respectively. Minocycline and tigecycline showed consistent active against 22 SXT-resistant strains. However, resistance rates were high in the remaining antimicrobial agents against SXT-resistant strains. In time-kill experiments, there were no synergisms in most drug combinations in time-kill experiments. SXT plus moxifloxacin displayed synergism when strains with low moxifloxacin MICs. Moxifloxacin plus Minocycline and moxifloxacin plus tigecycline displayed synergism in few strains. No antagonisms were found in these combinations. Overall, compared with single drug, the drug combinations demonstrated lower bacterial concentrations. Some combinations showed bactericidal activity. CONCLUSIONS: In S. maltophilia infections, susceptibility testing suggests that minocycline and SXT may be considered first-line therapeutic choices while tigecycline, moxifloxacin, levofloxacin, and ticarcillin-clavulanate may serve as second-line choices. Ceftazidime, colistin, and chloramphenicol show poor active against S. maltophilia. However, monotherapy is inadequate in infection management, especially in case of immunocompromised patients. Combination therapy, especially SXT plus moxifloxacin, may benefit than monotherapy in inhibiting or killing S. maltophilia.

Relationship of Sulfamethoxazole Therapeutic Drug Monitoring to Clinical Efficacy and Toxicity: A Retrospective Cohort Study.

BACKGROUND: Trimethoprim/sulfamethoxazole (TMP/SMX) is the treatment of choice for infections caused by Pneumocystis jiroveci, Stenotrophomonas maltophilia, and Nocardia species, but the utility of therapeutic drug monitoring (TDM) is unclear. The objective of this study was to evaluate the association between peak sulfamethoxazole (SMX) serum levels and clinical outcomes to determine the utility of TDM of TMP/SMX. METHODS: This study was conducted in patients receiving treatment with TMP/SMX for culture-positive infection who underwent TDM from 2003 to 2013. Peak SMX levels were classified as below target (<100 mcg/mL), within target (100-150 mcg/mL), or above target (>150 mcg/mL). The effect of initial SMX levels on clinical outcomes was compared using propensity score adjusted multivariable Cox models. RESULTS: A total of 279 patients had SMX monitoring performed. The primary infecting organisms were P. jiroveci (47%) and S. maltophilia (38%). A majority of patients (74%) had an SMX peak level outside of the target range. Using direct regression propensity score adjustment, there was no significant difference between rates of clinical failure and initial peak SMX level (<100 mcg/mL versus 100-150 mcg/mL: hazard ratio 0.92, 95% confidence interval, 0.28-3.07 and >150 mcg/mL versus 100-150 mcg/mL: hazard ratio 1.92, 95% confidence interval, 0.72-5.09). Similarly, there was no relationship between SMX level and toxicity (P = 0.42). CONCLUSIONS: Sulfamethoxazole serum levels outside the target range were not associated with increased rates of clinical failure in patients treated with TMP/SMX. There was also no association found between peak SMX levels and rates of adverse events. Although this study cannot disprove that dose adjustments after the initial SMX peak level may have affected clinical outcomes, the results suggest that the utility of SMX TDM may be limited to a subset of patients and requires further prospective investigation.

Cross-reactivity between darunavir and trimethoprim-sulfamethoxazole in HIV-infected patients.

OBJECTIVE: Both darunavir (DRV) and trimethoprim-sulfamethoxazole (TMP-SMX) carry a sulfonamide moiety and a warning for this cross-reactivity is given in the label of DRV. The aim of this study was to investigate the potential cross-reactivity between both drugs. DESIGN: Retrospective cohort study with a nested case-control study. METHODS: HIV-infected patients that received DRV-containing antiretroviral therapy at any time during the period of their HIV infection were included. Patients with no history of TMP-SMX use were excluded. The incidence of a DRV allergy, according to the Naranjo probability scale, was investigated in patients with an allergy to TMP-SMX compared with those without such an allergy. In order to identify possible risk factors associated with a DRV allergy among patients allergic to TMP-SMX, a nested case-control study was subsequently performed. RESULTS: A total of 405 patients were included, of whom 79 (17.5%) had a history of allergy to TMP-SMX. A DRV allergy was seen in four patients (5.1%) with a TMP-SMX allergy compared with four (1.2%) without a TMP-SMX allergy (P = 0.05). Patients with a TMP-SMX allergy were at higher risk for a DRV allergy (odds ratio 4.29; 95% confidence interval, 1.05-17.56). No additional risk factors for a DRV allergy among patients allergic to TMP-SMX were identified in the nested case-control study. CONCLUSION: Although DRV allergy is uncommon, making cross-reactivity with TMP-SMX a rare clinical problem, it appears to exist more often in the background of a TMP-SMX allergy.

Trimethoprim and sulfamethoxazole transmembrane clearance during modeled continuous renal replacement therapy.

BACKGROUND/AIMS: There is limited data regarding trimethoprim (TMP)/sulfamethoxazole (SMX) continuous renal replacement therapy (CRRT) dosing. We aimed to estimate TMP/SMX transmembrane clearance (CLtm) during continuous hemofiltration (CH) and continuous hemodialysis (CD) to guide dosing. METHODS: Using an in vitro model, TMP/SMX sieving coefficients (SC) and saturation coefficients (SA) were determined with high-flux polyarylethersulfone and polyacrylonitrile-sodium methallyl sulfonate copolymer hemodiafilters at ultrafiltration/dialysate rates of 1, 2, 3, and 6 l/h. TMP/SMX CLtm was calculated using measured SC and SA. TMP/SMX CRRT doses were modeled using CLtm and published TMP/SMX pharmacokinetic parameters. RESULTS: TMP SC/SA during CH/CD were significantly higher than SMX SC/SA. During modeling, TMP 10 mg/kg/day and its corresponding SMX dose, 50 mg/kg/day, resulted in steady state TMP/SMX peak concentrations associated with efficacy against Pneumocystis jirovecii. CONCLUSIONS: CRRT resulted in greater TMP CLtm than SMX. TMP 10 mg/kg/day divided q12h may be an appropriate initial dose to consider in patients undergoing CRRT.

Urinary biomarkers of trimethoprim bioactivation in vivo following therapeutic dosing in children.

The antimicrobial trimethoprim-sulfamethoxazole (TMP-SMX) is widely used for the treatment of skin and soft-tissue infections in the outpatient setting. Despite its therapeutic benefits, TMP-SMX has been associated with a number of adverse drug reactions, which have been primarily attributed to the formation of reactive metabolites from SMX. Recently, in vitro experiments have demonstrated that TMP may form reactive intermediates as well. However, evidence of TMP bioactivation in patients has not yet been demonstrated. In this study, we performed in vitro trapping experiments with N-acetyl-l-cysteine (NAC) to determine stable markers of reactive TMP intermediates, focusing on eight potential markers (NAC-TMP adducts), some of which were previously identified in vitro. We developed a specific and sensitive assay involving liquid chromatography followed by tandem mass spectrometry for measurement of these adducts in human liver microsomal samples and expanded the methodology toward the detection of these analytes in human urine. Urine samples from four patients receiving TMP-SMX treatment were analyzed, and all samples demonstrated the presence of six NAC-TMP adducts, which were also detected in vitro. These adducts are consistent with the formation of imino-quinone-methide and para-quinone-methide reactive intermediates in vivo. As a result, the TMP component of TMP-SMX should be considered as well when evaluating adverse drug reactions to TMP-SMX.

Serum concentration of co-trimoxazole during a high-dosage regimen.

OBJECTIVES: Sulfamethoxazole and trimethoprim have been used for decades, yet high dosages are rarely reported. We aimed to measure blood concentrations of both molecules in this situation. METHODS: Between 2002 and 2010, 22 patients received two tablets of co-trimoxazole three times a day, equivalent to a daily dosage of 2400 mg of sulfamethoxazole and 480 mg of trimethoprim. The trimethoprim and sulfamethoxazole concentrations were determined 3 h after administration using ion-paired HPLC. RESULTS: In the presence of a negative control, which yielded no peaks at the retention times for trimethoprim and sulfamethoxazole, the mean ± SD value for sulfamethoxazole concentration was 161.01 ± 69.154 mg/L and the mean ± SD value for trimethoprim was 5.788 ± 2.74 mg/L. CONCLUSIONS: These concentrations are largely above the trimethoprim and sulfamethoxazole MIC distributions as well as the trimethoprim resistance clinical breakpoint (4 mg/L) reported by EUCAST in 2012 for most bacterial pathogens, including Gram-positive species such as Staphylococcus aureus. Our results support proposing a high-dosage regimen of co-trimoxazole as a suitable alternative for methicillin-resistant S. aureus infections.

Vitreous and Aqueous Penetration of Orally Administered Trimethoprim-Sulfamethoxazole Combination in Humans.

PURPOSE: To determine the penetration of orally administered trimethoprim (TMP)-sulfamethoxazole (SMX) into the aqueous and vitreous cavity of noninflamed human eyes. METHODS: Nine adult patients undergoing cataract surgery and 10 adult patients undergoing pars plana vitrectomy were given 3 doses of oral TMP-SMX every 12 hours before the surgery. Aqueous and blood samples were collected from patients undergoing cataract surgery; vitreous and blood samples were collected from patients undergoing vitrectomy. The levels of TMP and SMX were analyzed using high-performance liquid chromatography and were compared with the mean minimum inhibitory concentrations (MIC) of potential ocular pathogens. RESULTS: TMP-SMX was present in all samples. Among eyes undergoing cataract surgery, the mean concentrations of TMP in aqueous and blood were 0.341 ± 0.141 µg/mL (mean ± SD) and 1.501 ± 0.433 µg/mL and of SMX were 5.259 ± 0.929 µg/mL and 11.835 ± 2.100 µg/mL, respectively. Among eyes undergoing vitrectomy, the mean concentrations of TMP in vitreous and blood were 1.864 ± 0.807 µg/mL and 4.591 ± 2.979 µg/mL and of SMX were 5.910 ± 2.705 µg/mL and 39.289 ± 15.469 µg/mL, respectively. MIC levels were achieved against many bacterial pathogens, including methicillin-resistant Staphylococcus aureus. CONCLUSIONS: TMP-SMX penetrates both the aqueous and vitreous cavities when given orally. The components reach therapeutic inhibitory concentrations in the ocular cavity against many potential pathogens.