N-acetyl Sulfamethoxazole Research Articles

Population Pharmacokinetics of Trimethoprim/Sulfamethoxazole: Dosage Optimization for Patients with Renal Insufficiency or Receiving Continuous Renal Replacement Therapy.

The goal of the study was to describe the population pharmacokinetics of trimethoprim, sulfamethoxazole, and N-acetyl sulfamethoxazole in hospitalized patients. Furthermore, this study used the model to optimize dosing regimens of cotrimoxazole for Pneumocystis jirovecii pneumonia and in patients with renal insufficiency or with continuous renal replacement therapy (CRRT). This was a retrospective multicenter observational cohort study based on therapeutic drug monitoring (TDM) data from hospitalized patients treated with cotrimoxazole. We developed two population pharmacokinetic (POPPK) models: a model of trimethoprim and an integrated model with both sulfamethoxazole and N-acetyl sulfamethoxazole concentrations. Monte Carlo simulations were performed to determine the optimal dosing regimen. A total of 348 measurements from 168 patients were available. The estimated glomerular filtration rate (eGFR) and CRRT were included as covariates on the clearance of all three compounds. Cotrimoxazole TID 1,920 mg and b.i.d. 2,400 mg led to sufficient exposure for infections with P. jirovecii in patients without renal insufficiency. To reach equivalent exposure, a dose reduction of 33.3% is needed in patients with an eGFR of 10 mL/minute/1.73 m2 and of 16.7% for an eGFR of 30 mL/minute/1.73 m2. N-acetyl sulfamethoxazole accumulates in patients with a reduced eGFR. CRRT increased the clearance of sulfamethoxazole, but not trimethoprim or N-acetyl sulfamethoxazole, compared with the median clearance in the population. Doubling the sulfamethoxazole dose is needed for patients on CRRT to reach equivalent exposure.

Sulfamethoxazole-induced crystal nephropathy: characterization and prognosis in a case series

Cotrimoxazole (Trimethoprim/Sulfamethoxazole-SMX) is frequently used in critically ill and immunocompromised patients. SMX is converted to N-acetyl-sulfamethoxazole (NASM) and excreted by the kidneys. NASM may form crystals in urine, especially in acid urine, that may induce a crystalline nephropathy. However, the imputability of crystals in acute kidney injury (AKI) has not been proven. We aimed to assess whether NASM crystals may promote AKI and to investigate risk factors associated with NASM crystalline nephropathy. Patients from Ile-de-France, France who developed AKI under SMX treatment introduced during hospitalization and had a crystalluria positive for NASM crystals were selected. Patients with excessive preanalytical delay for crystalluria or missing data regarding SMX treatment were excluded. We used the Naranjo score to assess the causal relationship between SMX and the development of AKI in patients with positive NASM crystalluria. Fourteen patients were included. SMX was the probable cause of AKI for 11 patients and a possible cause for 3 patients according to Naranjo score. Patients were exposed to high doses of SMX (but within recommended ranges), and most of them had a preexisting chronic kidney disease and were hypoalbuminemic. Urine pH was mildly acid (median 5.9). AKI occured more rapidly than expected after introduction of SMX (median 4 days) and recovered rapidly after drug discontinuation in most, but not all, cases. SMX is a probable cause of crystalline nephropathy. Monitoring of crystalluria in patients exposed to SMX may be of interest to prevent the development of crystalline nephropathy. Approval number of the study: BPD-2018-DIAG-008.

Development and validation of an UPLC-MS/MS assay for the simultaneous quantification of seven commonly used antibiotics in human plasma and its application in therapeutic drug monitoring.

To develop and validate an UPLC-MS/MS assay for simultaneous determination of the total concentration of ceftazidime, ciprofloxacin, flucloxacillin, piperacillin, tazobactam, sulfamethoxazole, N-acetyl sulfamethoxazole and trimethoprim, and the protein-unbound concentration of flucloxacillin, in human plasma to be used for research and clinical practice. Sample pretreatment included protein precipitation with methanol. For the measurement of protein-unbound flucloxacillin, ultrafiltration was performed at physiological temperature. For all compounds, a stable isotopically labelled internal standard was used. Reliability of the results was assessed by participation in an international quality control programme. The assay was successfully validated according to the EMA guidelines over a concentration range of 0.5-100 mg/L for ceftazidime, 0.05-10 mg/L for ciprofloxacin, 0.4-125 mg/L for flucloxacillin, 0.2-60 mg/L for piperacillin, 0.15-30 mg/L for tazobactam, 1-200 mg/L for sulfamethoxazole and N-acetyl sulfamethoxazole, 0.05-10 mg/L for trimethoprim and 0.10-50 mg/L for unbound flucloxacillin. For measurement of total concentrations, the within- and between-day accuracy ranged from 90.0% to 109%, and 93.4% to 108%, respectively. Within- and between-day precision (variation coefficients, CVs) ranged from 1.70% to 11.2%, and 0.290% to 5.30%, respectively. For unbound flucloxacillin, within-day accuracy ranged from 103% to 106% and between-day accuracy from 102% to 105%. The within- and between-day CVs ranged from 1.92% to 7.11%. Results of the international quality control programme showed that the assay is reliable. The method provided reliable, precise and accurate measurement of seven commonly prescribed antibiotics, including the unbound concentration of flucloxacillin. This method is now routinely applied in research and clinical practice.

Microbe-mediated simultaneous nitrogen reduction and sulfamethoxazole/N-acetylsulfamethoxazole removal in lab-scale constructed wetlands

Constructed wetlands (CWs) are increasingly used to treat complex pollution such as nitrogen and emerging organic micropollutants from anthropogenic sources. In this study, the denitrification, anaerobic ammonium oxidation, dissimilatory nitrate reduction to ammonium, and nitrous oxide release rates following exposure to the frequently detected sulfonamides sulfamethoxazole (SMX) and its human metabolite, N-acetylsulfamethoxazole (N-SMX), were investigated in lab-scale CWs. Over a period of 190 d, the denitrification rates were noticeably inhibited in the SMX and N-SMX groups at week 5. Subsequently, the denitrification rates recovered, accompanied by an increase in the relevant nitrogen reduction and antibiotic resistance genes (ARGs). The composition of the microbial community also changed during this process. After the denitrification rates recovered, Burkholderia_Paraburkholderia and Gordonia exhibited a significant positive correlation with SMX exposure, which simultaneously reduced nitrate concentrations and degraded antibiotics. Burkholderia_Paraburkholderia is a key carrier of ARGs. Finally, nitrogen reduction (> 90%) and antibiotic removal (> 80%) also recovered in both SMX- and N-SMX-exposed lab-scale CWs during the operation, which revealed the interaction of SMX or N-SMX removal and nitrogen reduction.

First international quality control programme for laboratories measuring antimicrobial drugs to support dose individualization in critically ill patients.

ObjectivesInternational quality control (proficiency testing) programmes are instituted to safeguard the analytical performance of laboratories and to aid these laboratories in identifying sources of error in their analytical methods. We describe the first international quality control programme for antimicrobial agents that are frequently used in critically ill patients.MethodsSpiked plasma samples with ceftazidime, ciprofloxacin, flucloxacillin, piperacillin, sulfamethoxazole, N-acetyl sulfamethoxazole and trimethoprim were shipped to 22 laboratories from eight different countries. Acceptable accuracy by the performing laboratory was defined if measurements were within 80%–120% limits of the true weighed-in concentrations.ResultsA total of 81% of the measurements (ranging between 56% and 100%, dependent on drug) were within the 80%–120% limits of the true weighed-in concentrations.ConclusionsWe found a relatively good performance of the participating laboratories in measuring eight different antimicrobial drugs. Nevertheless, some of the antimicrobial drugs were not measured properly as up to 44% of the measurements was inaccurate depending on the drug. Our results emphasize the need for and utility of an ongoing quality control programme.

Sex-related differences in disposition of sulfamethoxazole, N-acetyl-sulfamethoxazole and trimethoprim in yellow catfish (Pelteobagrus fulvidraco) following a single oral administration

The aim of this present study was to explore the sex-related differences in disposition regularities of sulfamethoxazole (SMZ), N-acetyl-sulfamethoxazole (N-ac-SMZ) and trimethoprim (TMP) in male and female yellow catfish. Concentrations of target compounds were determined using a reliable HPLC-MS/MS approach, which was validated according to the guidelines defined by FDA. The results showed that there are significant sex-associated differences in SMZ concentrations of muscle with skin and liver, in N-ac-SMZ levels of muscle with skin and kidney, and in TMP concentrations of muscle with skin, liver and kidney. Whereas, no significant sex differences were also observed in SMZ, N-ac-SMZ and TMP levels of plasma, in SMZ concentrations of kidney and in N-ac-SMZ concentrations of liver. Longer residue time of N-ac-SMZ than SMZ was observed in male and female yellow catfish. Withdrawal time (WT) of SMZ (N-ac-SMZ as the marker residue) calculated by the WT 1.4 software, was 11 days (male) and 9 days (female), respectively. By contrast, WT of SMZ (SMZ as the marker residue) was 9 days (male) and 7 days (female), respectively. These results could serve as reference data for establishing disparate use regimen and drug withdrawal time of SMZ and TMP in male and female yellow catfish.

Distribution and fate of pharmaceuticals and their metabolite conjugates in a municipal wastewater treatment plant

Some pharmaceutical conjugates can be excreted into wastewaters at levels rivalling those of the parent compounds; however, little is known about this potential reservoir of pharmaceuticals to aquatic systems. We evaluated the occurrence and distribution of four different classes of pharmaceuticals and their metabolite conjugates in a wastewater treatment plant over four months. Aqueous and suspended solids fractions of primary, mixed liquor, secondary, and final effluent, along with return activated sludge, and waste activated sludge were assessed. The only conjugate not found in the final effluent was acetaminophen sulfate. Moreover, thyroxine and thyroxine glucuronide were the only compounds quantified in the suspended solids in the final effluent. Propranolol, propranolol sulfate, thyroxine, and thyroxine glucuronide all had no significant decreases in concentration going through the wastewater treatment process, from primary to final effluent. However, there were significant decreases observed for acetaminophen (99.8%), sulfamethoxazole (71%), N-acetyl sulfamethoxazole (59%), and sulfamethoxazole glucuronide (79%). The mean (±SEM) mass loadings in the aqueous fraction of the final effluent for each compound ranged from 0.84 ± 0.2 g/d for thyroxine to 45.3 ± 4.2 g/d for acetaminophen. At least as much conjugate was released into receiving waters, if not more: 1.6 ± 0.2 g/d for thyroxine glucuronide to 18.5 ± 4.5 g/d for sulfamethoxazole glucuronide, and 61.2 ± 9.6 g/d for N-acetyl sulfamethoxazole. Additionally, the mean loading of thyroxine was 0.29 ± 0.025 g/day and thyroxine glucuronide 1.8 ± 0.59 g/day in the suspended solids. This equates to 26% of total thyroxine and 53% of total thyroxine glucuronide associated with suspended particulate matter that reaches receiving waters. This study reflects the importance of including phase II conjugates in assessing overall compound load of pharmaceutical discharge from wastewaters, and also that substantial amounts of such contaminants are associated with wastewater solids when drugs are in the pg/L to μg/L range.

Impact of sludge treatments on the extractability and fate of acetyl sulfamethoxazole residues in amended soils

Sludge recycled in agriculture may bring antibiotics into cropped soils. The nature, total amount, and availability of the antibiotics in soil partly depend on the sludge treatments. Our paper compares the fate of N-acetyl sulfamethoxazole (AC-SMX) residues between soils incubated with the same sludge but submitted to different processes before being added in soil.The fate of 14C-AC-SMX residues was studied in mixtures of soil and sludges at different treatment levels: 1) activated and 2) centrifuged sludges, both enriched with 14C-AC-SMX, and 3) limed and 4) heat-dried sludges obtained by treating the previously contaminated centrifuged sludge. The evolution of the extractability of 14C residues (CaCl2, methanol) and their mineralization were followed during 119 days.More than 80% of the initial 14C-activity was no longer extractable after 14 days, except in soil with limed sludge. Liming and drying the centrifuged sludge decreased the mineralized 14C fraction from 5.7-6.4% to 1.2–1.8% and consequently, the corresponding soils contained more 14C residues after 119 days. Although 14C residues were more CaCl2-extractable in soil with limed sludge, they seemed to be poorly bioavailable for biodegradation. For all solid sludges, the mineralization rate of 14C-AC-SMX residues was strongly correlated to that of sludge organic carbon, with a coefficient three times lower for the limed and dried sludges than for the centrifuged sludge after 14 days.

Fate of sulfamethoxazole, its main metabolite N-ac-sulfamethoxazole and ciprofloxacin in agricultural soils amended or not by organic waste products

Spreading organic waste products (OWP) issued from sewage sludge or manures into soil may disseminate antibiotics with unknown risks for human health and environment. Our objectives were to compare the fate of two sulfonamides, sulfamethoxazole (SMX) and its metabolite N-acetyl-sulfamethoxazole (N-ac-SMX), and one fluoroquinolone, ciprofloxacin (CIP), in an unamended soil, and two soils regularly amended since 1998 with a sewage sludge and green waste compost and with farmyard manure respectively. Incubations of soil spiked with 14C labelled SMX or N-ac-SMX (0.02 mg kg−1) or CIP (0.15 mg kg−1) allowed a quantification of radiolabeled molecules in the mineralized, easily, hardly and non-extractable fractions after 3 and 156 days. Nature of 14C molecules was also analyzed by HPLC in extractable fractions after 3 and 156 days.SMX and N-ac-SMX dissipation was fast and due to i) mineralization (∼10% of recovered 14C after 156 days) or incomplete degradation (production of metabolites), ii) adsorption, even if both sulfonamides present low Kd (<3 L kg−1) and iii) formation of non-extractable residues (NER), representing more than 50% of recovered radioactivity.N-ac-SMX was more mineralized than SMX, and formed more progressively NER, after a step of deacetylation. Adsorption of CIP was fast and formed mainly NER (>72%) whereas its mineralization was negligible. Repeated applications of OWP tend to enhance adsorption of antibiotics and lower their degradation, through the quantity and quality of the built up soil organic matter. If applications of sewage sludge compost favor adsorption and inhibit mineralization, applications of manure boost the formation of non-extractable residues.

Direct Photolysis of Human Metabolites of the Antibiotic Sulfamethoxazole: Evidence for Abiotic Back-Transformation

The presence of potentially persistent and bioactive human metabolites in surface waters gives rise to concern; yet little is known to date about the environmental fate of these compounds. This work investigates the direct photolysis of human metabolites of the antibiotic sulfamethoxazole (SMX). In particular, we determined photolysis kinetics and products, as well as their concentrations in lake water. SMX, N-acetyl sulfamethoxazole, sulfamethoxazole β-D-glucuronide, 4-nitroso sulfamethoxazole, and 4-nitro sulfamethoxazole were irradiated under various light sources and pH conditions. All investigated metabolites, except sulfamethoxazole β-D-glucuronide were found to be more photostable than SMX under environmentally relevant conditions. Between two and nine confirmed photoproducts were identified for SMX-metabolites through ultraperformance liquid chromatography/high-resolution mass spectrometry. Interestingly, photolytic back-transformation to SMX was observed for 4-nitroso-SMX, indicating that this metabolite may serve as an environmental source of SMX. Moreover, two human metabolites along with SMX were regularly detected in Lake Geneva. The knowledge that some metabolites retain biological activity, combined with their presence in the environment and their potential to retransform to the parent compound, underlines the importance of including human metabolites when assessing the effects of pharmaceuticals in the environment.

Primaquine Phosphate as a Promising Substitute for N-(1-Naphthyl)ethylenediamine. II. Analysis of Sulfa Drugs in Pharmaceutical Dosage Forms and Biological Samples.

A simple and sensitive spectrophotometric method for the determination of sulfonamides in bulk, in pharmaceutical dosage forms and in biological fluids was developed. The method is based on coupling the diazotized sulfa with the anti-malarial ingredient, primaquine phosphate, in an acid medium. The resulting orange color is stable for several weeks and has an absorption maximum between 468 - 474 nm, depending on the sulfa drug. The effect of different variables on color development was studied. Calibration graphs were established in the concentration range of 0.1 to 12 µg/ml with a minimum detection limit of 0.05 µg/ml. The molar absorptivities were in the range of 47589 - 66414 l mol-1 cm-1 , depending upon the sulfa drug. The percentage recoveries of sulfa drugs in dosage forms were in the range of 97.4 to 104.0%. The method was also utilized in the determination of sulfamethoxazole and N-acetyl sulfamethoxazole in serum and urine samples.