Total Antibiotic Concentration Research Articles

Antibiotics in a general population: Relations with gender, body mass index (BMI) and age and their human health risks

Recently, increasing regulatory and public attention has been paid to the exposure risks of antibiotics due to their occurrence and antibiotic resistance worldwide. However, limited information on antibiotic levels in general populations is available. Forty antibiotics, including 9 sulfonamides, 5 fluoroquinolones, 4 macrolides, 4 tetracyclines, 3 chloramphenicols, 12 β-lactams and 3 others, were analyzed in 107 serum samples of normal adults collected from a hospital in Dalian, North China, between 2015 and 2016 using solid-phase extraction (SPE) coupled with HPLC-MS/MS. The results clearly showed that antibiotics were present in the serum of these adults. Specifically, 28 antibiotics were detected in the samples, with detection frequencies ranging from 0.9% to 17.8%. The total antibiotic concentrations in 26.2% of the serum samples were between the LOD and 20.0ng/mL. Importantly, the maximum concentrations of 5 antibiotics (trimethoprim, ciprofloxacin, cefaclor, lincomycin and erythromycin) were above 1000ng/mL in 3.7% of the samples. Furthermore, the detection frequencies of 5 veterinary antibiotics, 7 human antibiotics and 16 human/veterinary antibiotics in the serum samples were 23.4%, 17.8% and 29.0%, respectively. Significant differences of the veterinary antibiotics between female and male adults and of the sulfonamides between different BMI (body mass index) groups were observed (p<0.05). The concentrations of sulfonamides in elderly individuals were significantly higher (p<0.05) than those in young people. Finally, our results showed that almost all of the adults had no health risks related to exposure to antibiotics at such levels despite the high effect ratio (ER=1.74) for azithromycin in one sample. This study is the first to report the current status of antibiotics in human blood, which can help in better understanding the long-term effects of antibiotics on general populations and in identifying susceptible populations that are at high risk to antibiotic exposure.

Antibiotics in the coastal water of the South Yellow Sea in China: Occurrence, distribution and ecological risks

The occurrence and distribution of 25 antibiotics from 5 categories in Yancheng coastal area of the South Yellow Sea were investigated using solid-phase extraction coupled with high-performance liquid chromatography tandem mass spectrometry. Results showed that these antibiotics were widely present in this region with the total concentration up to 1349.2ng/L. Fluoroquinolones and sulfonamides were the most abundant categories contributing 46.5%, and 21.4% to the total antibiotics burden. Trimethoprim was the antibiotic detected in all the samples. The detection rates of erythromycin-H2O, sulfamethoxazole and florfenicol were 70.0%, 56.7% and 53.4%, respectively. The distribution of antibiotics demonstrated a seaward decreasing trend with the attenuation rate ranging from 0.07 to 0.19km−1 in this region. Log total antibiotic concentrations was significantly correlated with DOC (dissolved organic carbon) contents, salinity and distance from the coast (p<0.05), which indicated the vital effect of these factors on the transport and fate of antibiotics. Risk assessment revealed that individual antibiotic could mainly pose a low to medium ecological risk, while the risk of antibiotic mixture on aquatic organisms needed further investigation.

Dynamics of antibiotic resistance genes in microbial fuel cell-coupled constructed wetlands treating antibiotic-polluted water

Microbial fuel cell-coupled constructed wetlands (CW-MFCs) use electrochemical, biological, and ecological functions to treat wastewater. However, few studies have investigated the risks of antibiotic resistance genes (ARGs) when using such systems to remove antibiotics. Therefore, three CW-MFCs were designed to assess the dynamics of ARGs in filler biofilm and effluent over 5000 h of operation. The experimental results indicated that relatively high steady voltages of 605.8 mV, 613.7 mV, and 541.4 mV were obtained at total influent antibiotic concentrations of 400, 1,000, and 1600 μg L−1, respectively. The 16S rRNA gene level in the cathode layer was higher than those in the anode and two middle layers, but the opposite trend was observed for the sul and tet genes. The relative abundance of the three tested sul genes were in the order sulI > sulII > sulIII, and those of the five tet genes were in the order tetA > tetC > tetW > tetO > tetQ. The levels of sul and tet genes in the media biofilm showed an increase over the treatment period. The effluent water had relatively low abundances of sul and tet genes compared with the filler biofilm. No increases were observed for most ARGs over the treatment period, and no significant correlations were observed between the ARGs and 16S rRNA gene copy numbers, except for sulI and tetW in the effluent. However, significant correlations were observed among most of the ARG copy numbers.

Wound Penetration of Cefazolin, Ciprofloxacin, Piperacillin, Tazobactam, and Vancomycin During Negative Pressure Wound Therapy.

Objective: Negative pressure wound therapy (NPWT) uses subatmospheric pressure as a noninvasive adjunct to treat wounds and has demonstrated clinical efficacy by accelerating healing of a variety of acute and chronic wounds. NPWT may also play a role in preventing or treating wound infections, possibly by increasing wound penetration of antibiotics. However, clinical data in patients undergoing antibiotic and NPWT treatment are limited. Approach: To evaluate the wound penetration of antibiotics in NPWT patients, we conducted a prospective, observational study of burn and trauma patients treated with NPWT and systemic antibiotics. We evaluated the plasma pharmacokinetic profile of systemic vancomycin, ciprofloxacin, cefazolin, and piperacillin/tazobactam, as well as total and unbound antibiotic concentrations in wound exudate from the same patients. Results: Data from 32 patients with 37 wounds undergoing NPWT demonstrated that vancomycin, ciprofloxacin, and piperacillin/tazobactam all penetrated wounds with exudate to plasma concentration ratios more than 0.8. Cefazolin did not penetrate wounds in patients undergoing NPWT as effectively, with an average exudate to plasma concentration ratio of 0.51. Innovation: Clinical data on the wound penetration of antibiotics in patients undergoing NPWT are limited, but these data suggest that antibiotics have different capacities for wound penetration during NPWT that should be considered when making clinical decisions. Conclusion: This initial report suggests that (1) vancomycin, ciprofloxacin, and piperacillin/tazobactam effectively penetrate wounds during NPWT and (2) cefazolin as well as other antibiotics may not penetrate wounds during NPWT.

Distribution and Risk Assessment of Antibiotics in a Typical River in North China Plain.

We evaluated the occurrence and distribution of 12 antibiotics from the sulfonamide (SAs), fluoroquinolone (FQs) and tetracycline (TCs) groups in the Weihe River, North China. The total antibiotic concentrations in surface water, pore water, and sediment samples ranged from 11.1 to 173.1ng/L, 5.8 to 103.9ng/L, and 9.5 to 153.4μg/kg, respectively. The values of the sediment-water partitioning coefficient in the Weihe River varied widely, from not detected to 943, 2213, and 2405L/kg for SAs, FQs, and TCs, respectively. The values of the partitioning coefficients between sediment and surface water were generally lower than those between sediment and pore water, which indicated ongoing inputs to the water. The risk assessment showed that there were relatively high ecological risks to aquatic algae in this area from sulfamethoxazole, norfloxacin, tetracycline, ofloxacin, and ciprofloxacin.

Antibiotics in water and sediments from Liao River in Jilin Province, China: occurrence, distribution, and risk assessment

The seasonal and spatial variations of 12 selected antibiotics belonging to four groups, including sulfonamides, quinolones, tetracyclines, and macrolides, were investigated in three main tributaries of Liao River in Jilin Province, northeast China. The concentrations of the antibiotics in the surface water and surface sediments were determined by HPLC–MS/MS. The results indicated that oxytetracycline (OTC), erythromycin (ETM), and ofloxacin (OFL) were dominant antibiotics in the water, with mean concentration of 174.9 ± 266.9, 103.2 ± 95.5, and 67.1 ± 77.3 ng/L, respectively, while OFL, OTC, and norfloxacin were prominent antibiotics in sediments, with mean concentration of 152.2 ± 108.3, 149.5 ± 147.6, and 62.8 ± 83.3 ng/g, respectively. The total antibiotic concentrations in water at each sampling site were 1.2–3 times higher in autumn (November 2015) than those in summer (July 2015), whereas antibiotic concentrations in sediments showed no significant seasonal variation. The highest total antibiotic concentrations in water and sediments were observed around cities with large populations of humans and livestock. Risk assessment based on single antibiotic exposure revealed that OFL, ETM, and OTC were main antibiotics with potential adverse ecological consequences for aquatic organisms. In addition, the mixtures of selected antibiotics posed medium to high risk for aquatic organisms in the Liao River in Jilin Province.

Pharmacokinetics of Intraperitoneal Cefalothin and Cefazolin in Patients Being Treated for Peritoneal Dialysis-Associated Peritonitis.

♦ The standard treatment of peritoneal dialysis (PD)-associated peritonitis (PD-peritonitis) is intraperitoneal (IP) administration of antibiotics. Only limited data on the pharmacokinetics and appropriateness of contemporary dose recommendations of IP cefalothin and cefazolin exist. The aim of this study was to describe the pharmacokinetics of IP cefalothin and cefazolin in patients treated for PD-peritonitis. ♦ As per international guidelines, IP cefalothin or cefazolin 15 mg/kg once daily was dosed with gentamicin in a 6-hour dwell to patients with PD-peritonitis during routine care. Serial plasma and PD effluent samples were collected over the first 24 hours of therapy. Antibiotic concentrations were quantified using a validated chromatographic method with pharmacokinetic analysis performed using a non-compartmental approach. ♦ Nineteen patients were included (cefalothin n = 8, cefazolin n = 11). The median bioavailability for both antibiotics exceeded 92%, but other pharmacokinetic parameters varied markedly between antibiotics. Both antibiotics achieved high PD effluent concentrations throughout the antibiotic dwell. Cefazolin had a smaller volume of distribution compared with cefalothin (14 vs 40 L, p = 0.003). The median trough total plasma antibiotic concentration for cefazolin and cefalothin during the dwell differed (plasma 56 vs 13 mg/L, p < 0.0001) despite a similar concentration in PD effluent (37 vs 38 mg/L, p = 0.58). Lower antibiotic concentrations were noted during PD dwells not containing antibiotic, particularly cefalothin, which was frequently undetectable in plasma and PD effluent. The median duration that the unbound antibiotic concentration was above the minimum inhibitory concentration (MIC) was approximately 13% (plasma) and 25% (IP) for cefalothin, and 100% (plasma and IP) for cefazolin, of the dosing interval. ♦ When IP cefalothin or cefazolin is allowed to dwell for 6 hours, sufficient PD effluent concentrations are present for common pathogens during this time. However, with once-daily IP dosing, in contrast to cefazolin, there is a risk of subtherapeutic plasma and PD effluent cefalothin concentrations, so more frequent dosing may be required.

The distribution of veterinary antibiotics in the river system in a livestock-producing region and interactions between different phases.

The occurrence of six common antibiotics in the surface water, sediment, and suspended particulate matter (SPM) of the Jiyun River, a typical river in the livestock-producing region in Beijing, northern China, was investigated. The results revealed that the antibiotics were widely distributed in the studied area. The aqueous samples were contaminated by the antibiotics, and the target antibiotics presented in highest levels were sulfonamides, with maximum concentrations of 230 and 385ng/L for sulfadiazine and sulfamethoxazole, respectively. Oxytetracyline, one of the tetracylines, was the most frequently detected compound in the particulate phase with maximum concentration of 121 and 130ng/g in the sediment and SPM, respectively. The total antibiotic concentration in the water was higher in the tributary than that in the main river, demonstrating that the tributaries were discharging antibiotics into the main river. In addition, the partition coefficients of sediment-water (Kp(S)) and the SPM-water (Kp(SPM)) were calculated. Overall, the Kp(S) decreases with an increase in the contents of SPM. In terms of the interaction between SPM and water, linear relationship between logarithm of Kp(SPM) (log Kp(SPM)) and the logarithm of molecular weight (log MW) was obtained, suggesting that large and heavy molecules are more likely to be attracted to suspended particulates, eventually leading to their enrichments in bed sediments.

The role of class I integrons in the dissemination of sulfonamide resistance genes in the Pearl River and Pearl River Estuary, South China

Antibiotic resistance genes (ARGs), as a newly emerging contaminant, are unique because they are disseminated through horizontal gene transfer in the environment. In the present study, a class 1 integron gene (int1) and various ARGs (sul1, sul2, sul3, qnrS, and ermB) were measured in water and sediment samples from the Pearl River (PR) to the Pearl River Estuary (PRE), where there is a distinct gradient in anthropogenic impact. The int1, sul1, and sul2 genes were detected in all samples, and their concentrations exhibited a clear trend of decline consistent with anthropogenic impact. Both the int1 and sul genes had dynamically migrated between water and sediments. The relative abundance of the int1 gene normalized to the 16S rRNA gene correlated significantly with the total concentrations of antibiotics in water and sediments. Good correlations were also observed between the abundance of int1 and each type of sul gene in the samples. However, the sul1 gene showed a much stronger relationship with int1 in different seasons, probably due to the presence of sul1 in the conserved region of class 1 integron. Our results strongly support that integrons play an important role in the dissemination of ARGs in human-impacted aquatic environments.

Sulfonamide antibiotics in the Northern Yellow Sea are related to resistant bacteria: Implications for antibiotic resistance genes

Antibiotic resistance gene (ARG) residues and the mode of transmission in marine environments remain unclear. The sulfonamide (SAs) concentrations, different genes and total bacterial abundance in seawater and sediment of the Northern Yellow Sea were analyzed. Results showed the genes sul I and sul II were present at relatively high concentrations in all samples, whereas the gene sul III was detected fewer. The ARGs concentrations in the sediment were 103 times higher than those in water, which indicated sediment was essential ARG reservoir. Statistical analysis revealed the total antibiotic concentration was positively correlated with the relative abundance of the gene sul I and sul II. The relative abundances of the gene sul I and the gene sul II were also correlated positively with those of the gene int1. This correlation demonstrated that SAs exerted selective pressure on these ARGs, whereas the gene int1 could be implicated in the propagation of the genes sul I and sul II in marine environments.

Variability in protein binding of teicoplanin and achievement of therapeutic drug monitoring targets in critically ill patients: Lessons from the DALI Study

The aims of this study were to describe the variability in protein binding of teicoplanin in critically ill patients as well as the number of patients achieving therapeutic target concentrations. This report is part of the multinational pharmacokinetic DALI Study. Patients were sampled on a single day, with blood samples taken both at the midpoint and the end of the dosing interval. Total and unbound teicoplanin concentrations were assayed using validated chromatographic methods. The lower therapeutic range of teicoplanin was defined as total trough concentrations from 10 to 20mg/L and the higher range as 10–30mg/L. Thirteen critically ill patients were available for analysis. The following are the median (interquartile range) total and free concentrations (mg/L): midpoint, total 13.6 (11.2–26.0) and free 1.5 (0.7–2.5); trough, total 11.9 (10.2–22.7) and free 1.8 (0.6–2.6). The percentage free teicoplanin for the mid-dose and trough time points was 6.9% (4.5–15.6%) and 8.2% (5.5–16.4%), respectively. The correlation between total and free antibiotic concentrations was moderate for both the midpoint (ρ=0.79, P=0.0021) and trough (ρ=0.63, P=0.027). Only 42% and 58% of patients were in the lower and higher therapeutic ranges, respectively. In conclusion, use of standard dosing for teicoplanin leads to inappropriate concentrations in a high proportion of critically ill patients. Variability in teicoplanin protein binding is very high, placing significant doubt on the validity of total concentrations for therapeutic drug monitoring in critically ill patients.

Occurrence, distribution and potential affecting factors of antibiotics in sewage sludge of wastewater treatment plants in China

The occurrence and distribution of eight quinolones, nine sulfonamides, and five macrolides were investigated in sewage sludge from 45 wastewater treatment plants in 23 cities in China. Among all the antibiotics considered, quinolones were the dominant antibiotics detected in all samples [total concentrations up to 8905μg/kg, dry weight (dw)], followed by macrolides (85.1μg/kg, dw), and sulfonamides (22.7μg/kg, dw). High concentrations of quinolones in sewage sludge indicated that antibiotics are widely used and extensive pollutants in China. Significant differences were observed for the total concentrations of antibiotics in sludge samples among the 45 WWTPs. To evaluate the potential factors affecting the antibiotic levels in sewage sludge, wastewater and sludge characteristics, as well as the operational conditions and treatment techniques in WWTPs were investigated. The results indicated that the antibiotic levels in sewage sludge depend to a great extent on wastewater characteristics. Significant correlation between total organic carbon (TOC) and total concentrations of antibiotics was also found in studied WWTPs, indicating that TOC could affect the sludge adsorption capability to the antibiotics to some extent. Moreover, the relation between treatment techniques and the total concentrations of antibiotics in sludge showed that antibiotic levels in sludge increased with longer solid retention time.

Antibiotics in the surface water of the Yangtze Estuary: Occurrence, distribution and risk assessment

The occurrence and distribution of five groups of antibiotics were investigated in the surface water of Yangtze Estuary over four seasons. Of the 20 antibiotics, only sulfamerazine was not detected at all sampling sites, indicating widespread occurrence of antibiotic residues in the study area. Detection frequencies and concentrations of antibiotics were generally higher in January, indicating that low flow conditions and low temperature might enhance the persistence of antibiotics in water. Antibiotic levels varied with location, with the highest concentrations being observed around river discharge and sewage outfall. Furthermore, a positive correlation between total antibiotic and DOC concentrations revealed the significant role played by DOC. Risk assessment based on single compound exposure showed that sulfapyridine and sulfamethoxazole could cause medium risk to daphnid in the Yangtze Estuary.

Accumulation of Pharmaceuticals, Enterococcus, and Resistance Genes in Soils Irrigated with Wastewater for Zero to 100 Years in Central Mexico

Irrigation with wastewater releases pharmaceuticals, pathogenic bacteria, and resistance genes, but little is known about the accumulation of these contaminants in the environment when wastewater is applied for decades. We sampled a chronosequence of soils that were variously irrigated with wastewater from zero up to 100 years in the Mezquital Valley, Mexico, and investigated the accumulation of ciprofloxacin, enrofloxacin, sulfamethoxazole, trimethoprim, clarithromycin, carbamazepine, bezafibrate, naproxen, diclofenac, as well as the occurrence of Enterococcus spp., and sul and qnr resistance genes. Total concentrations of ciprofloxacin, sulfamethoxazole, and carbamazepine increased with irrigation duration reaching 95% of their upper limit of 1.4 µg/kg (ciprofloxacin), 4.3 µg/kg (sulfamethoxazole), and 5.4 µg/kg (carbamazepine) in soils irrigated for 19–28 years. Accumulation was soil-type-specific, with largest accumulation rates in Leptosols and no time-trend in Vertisols. Acidic pharmaceuticals (diclofenac, naproxen, bezafibrate) were not retained and thus did not accumulate in soils. We did not detect qnrA genes, but qnrS and qnrB genes were found in two of the irrigated soils. Relative concentrations of sul1 genes in irrigated soils were two orders of magnitude larger (3.15×10−3±0.22×10−3 copies/16S rDNA) than in non-irrigated soils (4.35×10−5±1.00×10−5 copies/16S rDNA), while those of sul2 exceeded the ones in non-irrigated soils still by a factor of 22 (6.61×10–4±0.59×10−4 versus 2.99×10−5±0.26×10−5 copies/16S rDNA). Absolute numbers of sul genes continued to increase with prolonging irrigation together with Enterococcus spp. 23S rDNA and total 16S rDNA contents. Increasing total concentrations of antibiotics in soil are not accompanied by increasing relative abundances of resistance genes. Nevertheless, wastewater irrigation enlarges the absolute concentration of resistance genes in soils due to a long-term increase in total microbial biomass.

Correlation of tetracycline and sulfonamide antibiotics with corresponding resistance genes and resistant bacteria in a conventional municipal wastewater treatment plant

Antibiotics and corresponding resistance genes and resistant bacteria have been considered as emerging pollutants worldwide. Wastewater treatment plants (WWTPs) are potential reservoirs contributing to the evolution and spread of antibiotic resistance. In this study, total concentrations of tetracycline and sulfonamide antibiotics in final effluent were detected at 652.6 and 261.1ng/L, respectively, and in treated sludge, concentrations were at 1150.0 and 76.0μg/kg dry weight (dw), respectively. The quantities of antibiotic resistance genes and antibiotic resistant bacteria in final effluent were quantified in the range of 9.12×105–1.05×106 gene abundances /100mL (genomic copies/100mL) and 1.05×101–3.09×103CFU/mL, respectively. In treated sludge, they were quantified at concentrations of 1.00×108–1.78×109 gene abandances/100mL and 7.08×106–1.91×108CFU/100mL, respectively. Significant reductions (2–3 logs, p<0.05) of antibiotic resistance genes and antibiotic resistant bacteria were observed between raw influent and final effluent. The gene abundances of tetO and tetW normalized to that of 16S rRNA genes indicated an apparent decrease as compared to sulI genes, which remained stable along each treatment stage. Significant correlations (R2=0.75–0.83, p<0.05) between numbers of resistant bacteria and antibiotic concentrations were observed in raw influent and final effluent. No significance (R2=0.15, p>0.05) was found between tet genes (tetO and tetW) with concentration of tetracyclines identified in wastewater, while a significant correlation (R2=0.97, p<0.05) was observed for sulI gene and total concentration of sulfonamides. Correlations of the quantities of antibiotic resistance genes and antibiotic resistant bacteria with corresponding concentrations of antibiotics in sludge samples were found to be considerably weak (R2=0.003–0.07).

Tet and sul Antibiotic Resistance Genes in Livestock Lagoons of Various Operation Type, Configuration, and Antibiotic Occurrence

Although livestock operations are known to harbor elevated levels of antibiotic resistant bacteria, few studies have examined the potential of livestock waste lagoons to reduce antibiotic resistance genes (ARGs). The purpose of this study was to determine the prevalence and examine the behavior of tetracycline [tet(O) and tet(W)] and sulfonamide [sul(I) and sul(II)] ARGs in a broad cross-section of livestock lagoons within the same semiarid western watershed. ARGs were monitored for one year in the water and the settled solids of eight lagoon systems by quantitative polymerase chain reaction. In addition, antibiotic residues and various bulk water quality constituents were analyzed. It was found that the lagoons of the chicken layer operation had the lowest concentrations of both tet and sul ARGs and low total antibiotic concentrations, whereas sul ARGs were highest in the swine lagoons, which generally corresponded to the highest total antibiotic concentrations. A marginal benefit of organic and small dairy operations also was observed compared to conventional and large dairies, respectively. In all lagoons, sul ARGs were observed to be generally more recalcitrant than tet ARGs. Also, positive correlations of various bulk water quality constituents were identified with tet ARGs but not sul ARGs. Significant positive correlations were identified between several metals and tet ARGs, but Pearson's correlation coefficients were mostly lower than those determined between antibiotic residues and ARGs. This study represents a quantitative characterization of ARGs in lagoons across a variety of livestock operations and provides insight into potential options for managing antibiotic resistance emanating from agricultural activities.

Removal of antibiotics in conventional and advanced wastewater treatment: Implications for environmental discharge and wastewater recycling

Removal of 28 human and veterinary antibiotics was assessed in a conventional (activated sludge) and advanced (microfiltration/reverse osmosis) wastewater treatment plant (WWTP) in Brisbane, Australia. The dominant antibiotics detected in wastewater influents were cephalexin (med. 4.6 μg L −1, freq. 100%), ciprofloxacin (med. 3.8 μg L −1, freq. 100%), cefaclor (med. 0.5 μg L −1, freq. 100%), sulphamethoxazole (med. 0.36 μg L −1, freq. 100%) and trimethoprim (med. 0.34 μg L −1, freq. 100%). Results indicated that both treatment plants significantly reduced antibiotic concentrations with an average removal rate from the liquid phase of 92%. However, antibiotics were still detected in both effluents from the low-to-mid ng L −1 range. Antibiotics detected in effluent from the activated sludge WWTP included ciprofloxacin (med. 0.6 μg L −1, freq. 100%), sulphamethoxazole (med. 0.27 μg L −1, freq. 100%) lincomycin (med. 0.05 μg L −1, freq. 100%) and trimethoprim (med. 0.05 μg L −1, freq. 100%). Antibiotics identified in microfiltration/reverse osmosis product water included naladixic acid (med. 0.045 μg L −1, freq. 100%), enrofloxacin (med. 0.01 μg L −1, freq. 100%), roxithromycin (med. 0.01 μg L −1, freq. 100%), norfloxacin (med. 0.005 μg L −1, freq. 100%), oleandomycin (med. 0.005 μg L −1, freq. 100%), trimethoprim (med. 0.005 μg L −1, freq. 100%), tylosin (med. 0.001 μg L −1, freq. 100%), and lincomycin (med. 0.001 μg L −1, freq. 66%). Certain traditional parameters, including nitrate concentration, conductivity and turbidity of the effluent were assessed as predictors of total antibiotic concentration, however only conductivity demonstrated any correlation with total antibiotic concentration ( p=0.018, r=0.7). There is currently a lack of information concerning the effects of these chemicals to critically assess potential risks for environmental discharge and water recycling.

Effects of pharmaceuticals on Daphnia survival, growth, and reproduction

Pharmaceuticals have been globally detected in surface waters, and the ecological impacts of these biologically-active, ubiquitous chemicals are largely unknown. To evaluate the aquatic toxicity of individual pharmaceuticals and mixtures, we performed single species laboratory toxicity tests with Daphnia magna, a common freshwater zooplankton. We conducted acute (6-day) and chronic (30-day) exposure pharmaceutical bioassays and evaluated survivorship and morphology of adults and neonates, adult length, resting egg production, brood size (fecundity), and the proportion of male broods produced (sex ratio). In general, exposure to a single pharmaceutical in the 1–100 μg/l range yielded no apparent effects on the normal life processes of Daphnia. However, chronic fluoxetine exposure (36 μg/l) significantly increased Daphnia fecundity, and acute clofibric acid exposure (10 μg/l) significantly increased sex ratio. A mixture of fluoxetine (36 μg/l) and clofibric acid (100 μg/l) caused significant mortality; the same fluoxetine concentration mixed with 10 μg/l clofibric acid resulted in significant deformities, including malformed carapaces and swimming setae. Mixtures of three to five antibiotics (total antibiotic concentration 30–500 μg/l) elicited changes in Daphnia sex ratio. We conclude: (1) individual and mixtures of pharmaceuticals affect normal development and reproduction of Daphnia magna, (2) aquatic toxicity of pharmaceutical mixtures can be unpredictable and complex compared to individual pharmaceutical effects, and (3) timing and duration of pharmaceutical exposure influence aquatic toxicity.

Effects of sulfonamide and tetracycline antibiotics on soil microbial activity and microbial biomass

Increasingly often soil residual concentrations of pharmaceutical antibiotics are detected, while their ecotoxic relevance is scarcely known. Thus, dose related effects of two antibiotics, sulfapyridine and oxytetracycline, on microorganisms of two different topsoils were investigated. The fumigation-extracted microbial C ( E C) and ergosterol were determined to indicate soil microbial and fungal biomass, respectively. Microbial activity was tested as basal respiration (BR), dehydrogenase activity (DHA), substrate-induced respiration (SIR), and Fe(III) reduction. The BR and DHA were uninfluenced even at antibiotic concentrations of 1000 μg g −1. This revealed that an activation of microbial growth through nutrient substrate addition is required to test possible effects of the bacteriostatic antibiotics. In addition, the effects of both antibiotics were time dependent, showing that short-term tests were not suitable. Clear dose–response relations were determined with SIR when the short-term incubation of 4 h was extended into the growth phase of the microorganisms (24 and 48 h). The Fe(III) reduction test, with a 7-d incubation, was also found to be suitable for toxicity testing of antibiotics in soils. Effective doses inhibiting the microbial activity by 10% (ED 10) ranged from total antibiotic concentrations of 0.003–7.35 μg g −1, depending on the antibiotic compound and its soil adsorption. Effective solution concentrations (EC 10), calculated from distribution coefficients, ranged from 0.2 to 160 ng g −1. The antibiotics significantly ( p < 0.05) reduced numbers of soil bacteria, resulting in dose related shifts in the fungal:bacterial ratio, which increased during 14 d, as determined from analysis of ergosterol and E C. It was concluded that pharmaceutical antibiotics can exert a temporary selective pressure on soil microorganisms even at environmentally relevant concentrations.

Ceftriaxone pharmacokinetics during iatrogenic hydroxyethyl starch-induced hypoalbuminemia: a model to explore the effects of decreased protein binding capacity on highly bound drugs.

Although various drugs used by anesthesiologists highly bind to plasma proteins, the impact of iatrogenically induced hypoproteinemia on their pharmacologic effects has never been investigated. The authors determined the pharmacokinetics of ceftriaxone, a cephalosporin that binds strongly to albumin in postsurgical patients with hydroxyethyl starch-induced hypoalbuminemia. Eleven hypoalbuminemic (serum albumin < 25 g/l) patients and age (+/- 5 yr)-, sex-, and body surface area (+/- 10%)-matched healthy volunteers received a 2-g ceftriaxone dose infused over a 15-min period. Fourteen venous blood samples were collected during the 24-h study period. Free ceftriaxone concentrations were determined by ultrafiltration. Antibiotic concentrations in plasma and ultrafiltrate were measured by ion-paired reversed-phase chromatography. The pharmacokinetic parameters derived from total and free antibiotic concentrations were determined using a noncompartmental method. Data are expressed as median and range. The pharmacokinetic parameters derived from total ceftriaxone concentrations were similar for the two groups, except for the median corrected volume of distribution at steady state, which was increased (P = 0.05) to 0.18 l/kg (range, 0. 11-0.29 l/kg) in patients, compared with 0.15 l/kg (range, 0.13-0.22 l/kg) in volunteers. The area under the free ceftriaxone concentration-time curve was twice as high in patients as in volunteers (median 192, range 114-301 vs. median 122, range 84-169 h. mg-1. l-1;P = 0.03). Moreover, the free ceftriaxone concentration remained more than 4 mg/l during more time in patients (median, 16. 7; range, 12.6-21.4 vs. median, 11.1; range, 6.0-19.0 h; P = 0.03). Compared with healthy volunteers, patients with iatrogenic hypoalbuminemia have higher free ceftriaxone concentrations during the 24 h after antibiotic administration. This modification increases drug distribution into extravascular space and may enhance effectiveness.