How Should We Activate Ferrate(VI)? Fe(IV) and Fe(V) Tell Different Stories about Fluoroquinolone Transformation and Toxicity Changes.

Many studies have investigated activation of ferrate (Fe(VI)) to produce reactive high-valent iron intermediates to enhance the oxidation of micropollutants. However, the differences in the risk of pollutant transformation caused by Fe(IV) and Fe(V) have not been taken seriously. In this study, Fe(VI)-alone, Fe3+/Fe(VI), and NaHCO3/Fe(VI) processes were used to oxidize fluoroquinolone antibiotics to explore the different effects of Fe(IV) and Fe(V) on product accumulation and toxicity changes. The contribution of Fe(IV) to levofloxacin degradation was 99.9% in the Fe3+/Fe(VI) process, and that of Fe(V) was 89.4% in the NaHCO3/Fe(VI) process. The cytotoxicity equivalents of levofloxacin decreased by 1.9 mg phenol/L in the Fe(IV)-dominant process while they significantly (p < 0.05) increased by 4.7 mg phenol/L in the Fe(V)-dominant process. The acute toxicity toward luminescent bacteria and the results for other fluoroquinolone antibiotics also showed that Fe(IV) reduced the toxicity and Fe(V) increased the toxicity. Density functional theory calculations showed that Fe(V) induced quinolone ring opening, which would increase the toxicity. Fe(IV) tended to oxidize the piperazine group, which reduced the toxicity. These results show the different-pollutant transformation caused by Fe(IV) and Fe(V). In future, the different risk outcomes during Fe(VI) activation should be taken seriously.

Ecotoxicity of the fluoroquinolone antibiotic delafloxacin to the water flea Simocephalus vetulus and its offspring under the influence of calcium modulation.

Delafloxacin (DFX), one of the latest additions to the fluoroquinolone antibiotics, is gaining heightened recognition in human therapy due to its potential antibacterial efficacy in a wide range of applications. Concerns have arisen regarding its presence in the environment and its potential interactions with multivalent metals, such as calcium (Ca). The present study investigated the trans- and multigenerational effects of environmentally projected concentrations of DFX (100-400 µg DFX L-1) on individual- and population-level responses of parental S. vetulus (F0) and its descendants (F1) under normal (26 mg L-1) and high (78 mg L-1) Ca conditions. Exposure of the F0 generation to DFX under the normal Ca condition resulted in reduced juvenile body length (JBL), increased age-specific survival rate (lx), indicating prolonged developmental time, reduced age-specific fecundity rate (mx), and decreased population growth rate (rm). Under the high Ca condition, JBL, mx, and rm were adversely affected. Transgenerational effects of DFX existed, as F1 individuals exhibited persistent suppressions in at least one endpoint under both Ca conditions even after being transferred to a clear medium. Continuous exposure of the F1 generation to DFX had negative impacts on JBL, mx, and rm under the normal Ca condition, and on JBL and rm under the high Ca condition. However, cumulative effects were not observed, suggesting the potential development of tolerance to DFX in the F1 organisms. These findings suggest that DFX is a harmful compound for the non-target model organism S. vetulus and reveal a potential antagonism between DFX and Ca. Nevertheless, the interaction between other (fluoro)quinolones and Ca remains unclear, necessitating further research to establish this phenomenon more comprehensively, including understanding the interaction mechanism in ecotoxicological contexts.

Long-term exposure of Allonais inaequalis to a mixture of antibiotics in freshwater and synthetic wastewater matrices: Reproduction, recovery, and swimming responses.

Antibiotics from sulfonamide, fluoroquinolone, and diaminopyrimidine classes are widely used in human and veterinary medicine, and their combined occurrence in the aquatic environment is increasing around the world. In parallel, the understanding of how mixtures of these compounds affect non-target species from tropical freshwaters is scarce. Thus, this work aimed to study the long-term reproductive, recovery, and swimming effects of mixtures of 12 antibiotics from three different classes (up to 10 µg L-1 ) added to freshwater (FWM) and synthetic wastewater (SWM) matrices on freshwater worm Allonais inaequalis. Results revealed that at the reproduction level, the exposure to antibiotics in the SWM matrix does not cause a significant toxic effect on species after 10 days. On the other hand, exposures to initial dose mixtures (10 µg L-1 each) in FWM caused a significant reduction of offspring by 19.2%. In addition, recovery bioassays (10 days in an antibiotic-free environment) suggested that A. inaequalis has reduced offspring production due to previous exposure to antibiotic mixtures in both matrices. Furthermore, despite slight variation in swimming speed over treatments, no significant differences were pointed out. Regarding antibiotics in the water matrices after 10-day exposures, the highest concentrations were up to 2.7, 7.8, and 4.2 µg L-1 for antibiotics from sulfonamide, fluoroquinolone, and diaminopyrimidine classes, respectively. These findings suggest that a species positioned between primary producers and secondary consumers may experience late reproductive damage even in an antibiotic-free zone, after previous 10-day exposure to antibiotic mixtures. PRACTITIONER POINTS: A mixture of sulfonamide, fluoroquinolone, and diaminopyrimidine antibiotics in freshwater affects the offspring production of A. inaequalis after 10 days. After the 10-day antibiotic exposure, the reproduction of A. inaequalis remains affected in an antibiotic-free environment over the recovery period. The swimming speed of the worms does not change after 10 days of exposure to the antibiotic mixture. The concentration of dissolved solids can limit the natural degradation of sulfonamide, fluoroquinolone, and diaminopyrimidine antibiotics in the aquatic environment.

Pharmacokinetic model of human exposure to ciprofloxacin through consumption of fish.

Fluoroquinolones are broad-spectrum antibiotics that accumulate in the environment. To assess human exposure through the food chain, we developed a pharmacokinetic model of fluoroquinolone accumulation in fish and a human pharmacokinetic model to predict gastrointestinal concentrations of ciprofloxacin, a common fluoroquinolone, following consumption of fish. At 70 ng/L ciprofloxacin, the average in North American surface waters, the fish steady-state concentration was calculated to be 7.5 × 10-6 µg/g. Upon human consumption of the FDA-recommended portion of 113 g of fish containing this ciprofloxacin level, the predicted human intestinal concentration was 2 × 10-6 µg/mL. At 4 × 106 ng/L (4 µg/mL) ciprofloxacin, the highest recorded environmental measurement, these numbers were 0.42 µg/g in fish and 0.1 µg/mL in the human intestine. Thus, based on the ciprofloxacin MIC for E. coli of 0.13 µg/mL, background environmental ciprofloxacin levels are unlikely to be problematic, but environmental pollution can result in high intestinal levels that may cause gut dysbiosis and antibiotic resistance.

An optimized electro-fenton pretreatment for the degradation and mineralization of a mixture of ofloxacin, norfloxacin, and ciprofloxacin.

The electro-Fenton process (EFP) is a powerful advanced oxidation process beneficial to treating recalcitrant contaminants, and there has been a continuing interest in combining this technology to enhance the efficiency of conventional wastewater treatment processes. In this work, an optimized EFP process is performed as pretreatment for the degradation and mineralization of three blank fluoroquinolones (FQs) drugs: ofloxacin (OFL), norfloxacin (NOR), and ciprofloxacin (CIP). The optimization of the experiment was carried out using a Box-Behnken experimental design. Faster and complete degradation of the drugs mixture was achieved in 90 min with 61.12 ± 2.0% of mineralization in 180 min, under the optimized conditions: j = 244.0 mA cm-2, [Fe2+] = 0.31 mM, and [FQs] = 87.0 mg L-1. Furthermore, a low toxicity effluent was obtained in 90 min of the experiment, according to bioassay toxicity with Vibrio fischeri. Five short-chain carboxylic acids, including oxalic, maleic, oxamic, formic, and fumaric acids, were detected and quantified, in addition to F- and NO3- inorganic ions. The inhibition of the reactive oxygen species with scavenger proof was also evaluated in this paper.

Evaluation of drug-induced liver toxicity of trovafloxacin and levofloxacin in a human microphysiological liver model.

Drug-induced liver injury induced by already approved substances is a major threat to human patients, potentially resulting in drug withdrawal and substantial loss of financial resources in the pharmaceutical industry. Trovafloxacin, a broad-spectrum fluoroquinolone, was found to have unexpected side effects of severe hepatotoxicity, which was not detected by preclinical testing. To address the limitations of current drug testing strategies mainly involving 2D cell cultures and animal testing, a three-dimensional microphysiological model of the human liver containing expandable human liver sinusoidal endothelial cells, monocyte-derived macrophages and differentiated HepaRG cells was utilized to investigate the toxicity of trovafloxacin and compared it to the structurally-related non-toxic drug levofloxacin. In the model, trovafloxacin elicited vascular and hepatocellular toxicity associated with pro-inflammatory cytokine release already at clinically relevant concentrations, whereas levofloxacin did not provoke tissue injury. Similar to in vivo, cytokine secretion was dependent on a multicellular immune response, highlighting the potential of the complex microphysiological liver model for reliably detecting drug-related cytotoxicity in preclinical testing. Moreover, hepatic glutathione depletion and mitochondrial ROS formation were elucidated as intrinsic toxicity mechanisms contributing to trovafloxacin toxicity.

Comprehensive understanding of fluoroquinolone degradation via MPUV/PAA process: Radical chemistry, matrix effects, degradation pathways, and toxicity.

The wide occurrence of fluoroquinolones (FQs) in aquatic environments has aroused increasing concern about their potential adverse effects on human health. In this study, an emerging advanced oxidation process, i.e., the Medium-Pressure Ultraviolet/Peracetic Acid (MPUV/PAA) process, was used to degrade FQs (e.g., levofloxacin (LEV), norfloxacin, and ciprofloxacin). Compared with the MPUV process alone and the PAA process alone, the MPUV/PAA process significantly promoted degradation of FQs due to the considerable contribution of reactive radicals. Probe experiments revealed that PAA-specific organic radicals (e.g., CH3C(O)O• and CH3C(O)OO•) were the major radicals responsible for FQ elimination. Rapid degradation of FQs via the MPUV/PAA process was achieved within a wide range of pH values (5-9) by selecting LEV as the target compound, and higher pH values were more favorable for the reaction. The slight impacts of Cl- and CO32-/HCO3- on LEV removal were observed. The transformation products and pathways of LEV were identified, and nearly all of the transformation pathways occurred on the piperazine ring. Based on Quantitative Structure-Activity Relationship (QSAR) analysis, most of the products had lower toxicities than LEV. Overall, these findings improve our understanding and application of the MPUV/PAA process for degrading emerging contaminants in (waste)water treatment.

Occurrence, distribution and risk assessment of antibiotics at various aquaculture stages in typical aquaculture areas surrounding the Yellow Sea.

The pollution of antibiotics commonly existed throughout the entire aquaculture process, but the residues of antibiotics at different aquaculture stages have rarely been studied. This study investigated the occurrence, distribution and risk assessment of antibiotics at different aquaculture stages (the non-aquaculture stage, the early aquaculture stage, the middle aquaculture stage, and the late aquaculture stage) in two typical marine aquaculture areas (Mahegang River and Dingzi Bay) surrounding the Yellow Sea. Fluoroquinolones and tetracyclines were commonly used antibiotics in the aquaculture of these areas with high detection frequencies (17% to 83%). Compared among four aquaculture stages, the highest concentration of antibiotics (9032.08 ng/L) in aquaculture ponds was detected at the late aquaculture stage. And the antibiotic pollution level of natural water was directly related to the aquaculture stages. Similarly, at the aquaculture stages, the detection frequency of antibiotics in sediments was higher than that at the non-aquaculture stage. Based on the correlation analysis, the concentration of main antibiotics in water showed a positive correlation with total nitrogen (p<0.05) and chlorophyll a (p<0.01), while it showed a negative correlation with salinity (p<0.01) in coastal water of the Dingzi Bay. According to the risk assessment, with the development of aquaculture stages, the selection pressure of fluoroquinolones and tetracyclines on resistant bacteria had increased. And the ecological risks caused by sulfonamides and tetracyclines to aquatic organisms had also increased markedly. Overall, this study may provide a reference for formulating regulatory policies regarding antibiotic use at different aquaculture stages.

Designing benign molecules: The influence of O-acetylated glucosamine-substituents on the environmental biodegradability of fluoroquinolones.

Antibiotics are detected worldwide in the aquatic environment, with continuously rising concentrations. Antibiotics in the environment have the potential to damage ecosystems and contribute to the development of resistance. Whilst a few antibiotics, such as some ß-lactams, are eliminated by effluent treatment, others, such as fluoroquinolones, are not or just partially removed and enter the environment. Therefore, approaches are needed to tackle those problems at the compound level. Benign by design (BbD), an important part of green pharmacy, has the goal to integrate environmental fate and end-of-use considerations at the very beginning, i.e., into the design of active pharmaceutical ingredients. Hence, pharmaceuticals should be designed to be sufficiently active and stable during storage and usage but should degrade after excretion into the environment, so that they cannot cause any adverse effects. Fluoroquinolones (FQs) are important broad-spectrum antibiotics. They are known to be persistent in the environment and to be neither inactivated nor degraded or even mineralized during sewage treatment. The addition of new substituents via amidation, like glucosamine moieties, at the carboxylic group of FQs, led to better antimicrobial activity compared to its parent compounds against various microorganisms. To investigate if the addition of sugar moieties could improve the overall environmental biodegradability of FQs, eight novel quinolone and fluoroquinolone analogs conjugated with 1,3,4,6-Tetra-O-acetyl-ß-d-glucosamine and 2-deoxy-d-glucopyranose have been investigated regarding their ready biodegradability (OECD 301D/F) and their degradation pathways have been analyzed. According to the OECD 301D test, none of the substances could be classified as readily biodegradable. However, the O-acetyl analogs did undergo a partial degradation of the O-acetyl glucosamine moiety, via stepwise deacetylation and the degradation of the whole glucosamine moiety. The degradation resulted in Fluoroquinolone-3-carboxamide derivatives. Those insights could be further used as input for fragment-based design of benign APIs that will degrade once they reached the environment.

Determinants of the exposure of Eurasian griffon vultures (Gyps fulvus) to fluoroquinolones used in livestock: The role of supplementary feeding stations.

Veterinary pharmaceuticals, including antibiotics, are emerging contaminants of concern worldwide. Avian scavengers are exposed to pharmaceuticals through consumption of livestock carcasses used for feeding wildlife for conservation purposes at supplementary feeding stations. Here we tested the hypothesis that griffon vultures (Gyps fulvus) would be more exposed to antibiotics (i.e., quinolones) when feeding on livestock carcasses from intensive farming than when they rely on carcasses from extensive farming or wild animals. We sampled 657 adult griffon vultures captured between 2008 and 2012. In addition, we sampled tissues from domestic livestock supplied at feeding stations in the study area between 2009 and 2019; pig (n = 114), sheep (n = 28), cow (n = 1) and goat (n = 2). Samples were analysed by liquid chromatography with electrospray ionization mass spectrometry (LC-ESI-MS). Quinolones were detected in plasma from 12.9% of the griffon vultures analysed. Quinolone prevalence in griffon vultures varied significantly among feeding stations but was also affected by the total amount of carcasses supplemented, especially the mass of pig carcasses. These results aligned with a 21.1% quinolone prevalence in pig carcasses sampled at feeding stations, wherein enrofloxacin and ciprofloxacin levels of up to 3359 ng/g and 1550 ng/g, respectively, were found. Given enrofloxacin pharmacokinetics in pig tissues, 5.3% of the analysed pigs may have died no more than one day after treatment. Quinolone presence in vultures was negatively associated with blood lead levels, which mostly originates from lead ammunition and indicates a higher consumption of game animal carcasses. Carcass disposal for feeding avian scavengers must always assess and manage the risks posed by veterinary pharmaceuticals, especially when livestock provided may have died soon after treatment.

Efficient and synergistic degradation of fluoroquinolones by bacteria and microalgae: Design of environmentally friendly substitutes, risk regulation and mechanism analysis.

Fluoroquinolones (FQs) are widely used as antimicrobial agents, and their nonbiodegradable in sewage has become an increasingly concerning. High-biochemical substitutes of FQs were designed with bacteria and microalgae as driving forces of biodegradation, and this is the first study on efficient synergistic degradation of FQs by multiple microorganisms. Among 143 designed FQ substitutes, only one was screened with high biodegradability (increased by 120.51 %), improved functional properties (genotoxicity: 13.66 %), less environmental impacts (bio-accumulation: -44.81 %), less human health and ecological risk (hepatotoxicity: -106.21 %). The complex functional protein with the synergistic degradation effect of bacteria and microalgae was constructed, which proved their synergistic degradation and realized the effect of "1 + 1 > 2″. The best risk regulation scheme determined using molecular dynamics simulation proved the degradation ability of complex functional protein and found the CIP-129 was easy to be degraded in real environment compared with CIP, and the degradation rate increased by 70.42 %. The synthesis path of CIP-129 and CIP were inferred and calculated, and the results showed the Gibbs free energies of three CIP-129 synthetic paths (40.64 a.u.; 40.61 a.u.; 40.65 a.u.) were close to the energy required for the CIP (39.43 a.u.), indicating there was no significant difference in the energy consumption of CIP-129 in laboratory synthesis.

Ecotoxicological effects of human and veterinary antibiotics on water flea (Daphnia magna).

In the present study, we assessed the ecotoxicological effects of selected human and veterinary antibiotics to D. magna. Ecological risk assessment was done by calculating the risk quotients (RQs) of the antibiotics to the species. Results showed that enrofloxacin, a veterinary fluoroquinolone antibiotic, was the most toxic against D. magna with a 48 h EC50 value of 28.59 mg/l. The binary mixture of fluoroquinolones was also more toxic to the species than binary mixtures of macrolides. Fecundity in organisms in negative control was higher than fecundity in organisms exposed to environmentally relevant concentrations of the four antibiotics. Enrofloxacin also has a moderate risk to the species with RQ values of 0.199 and 0.416 in surface waters and wastewaters, respectively. Antibiotics pose a greater ecological risk when present in mixtures in the aquatic environment. Environmental standards for pharmaceuticals should incorporate mixture toxicity data to ensure accurate protection of non-target organisms in polluted environments.

Toxicity, biodegradation of moxifloxacin and gatifloxacin on Chlamydomonas reinhardtii and their metabolic fate.

The novel fourth-generation fluoroquinolones (FQs) were developed to improve the antimicrobial activity and their utilization has rapidly increased in recent years. However, knowledge of the ecotoxicity and microalgae-mediated biodegradation of these novel FQs is limited. In this research, the toxic effects of moxifloxacin (MOX) and gatifloxacin (GAT) on Chlamydomonas reinhardtii as well as their biodegradation and metabolic fate were investigated. The results showed that the toxicity of MOX to C. reinhardtii was higher than that of GAT, and increased with culture time. Chlorophyll fluorescence and pigment content analyses suggested that the decrease in photosynthetic efficiency was primarily caused by the inhibition of electron transport after QA in PSII complex. These FQs induced oxidative damage in cells, and the antioxidation mechanisms of C. reinhardtii were analyzed. The maximum MOX removal of 77.67% by C. reinhardtii was achieved at 1 mg/L MOX, whereas the maximum GAT removal of 34.04% was attained at 20 mg/L GAT. The different hydrophilicity and lipophilicity of these FQs resulted in distinct findings in biodegradation experiments. Identification of the transformation products suggested that the likely biodegradation pathways of FQs by C. reinhardtii were hydroxylation, demethylation, and ring cleavage.

Magnetic visible-light activated photocatalyst ZnFe2O4/BiVO4/g-C3N4 for decomposition of antibiotic lomefloxacin: Photocatalytic mechanism, degradation pathway, and toxicity assessment.

Magnetic ZnFe2O4/BiVO4/g-C3N4 (ZBC) composites were prepared via a facile hydrothermal and calcination method for the degradation of a representative antibiotics lomefloxacin (LFX) under visible light irradiation. The optimal photocatalyst ZBC-10 with a ZnFe2O4:BiVO4:g-C3N4 mass ratio of 1:8:10 performed 96.1% removal of LFX after 105 min of illumination. The excellent performance is ascribed to the effective construction of heterojunctions and its capacity to form a double Z-scheme charge transmission pathway among the hosts in ZBC-10. The composite enhanced the separation and migration of photoexcited charge carriers and the effective generation of multiple active radicals including ·OH, ·O2-, and 1O2. The LFX degradation process, identified based on an integrated HPLC-Q-TOF-MS analysis and density functional theory computation of the Fukui indices, comprised of three pathways initiated by the opening of the piperazinyl ring, separation of piperazinyl and quinoline moieties, and cleavage of the pyridine ring on the quinoline moieties. Ecotoxicological evaluation confirmed the reduced toxicity of transformation intermediates over photocatalysis. Convenient magnetic recovery, high performance, and high recyclability made ZBC-10 a promising visible-light-activated photocatalyst for practical implementation in eliminating antibiotics from wastewater.

Fluoroquinolone antibiotics disturb the defense system, gut microbiome, and antibiotic resistance genes of Enchytraeus crypticus.

Antibiotic residues from animal manure cause soil pollution and can pose a threat to soil animals. In this study, the toxicological effects of fluoroquinolone antibiotics on Enchytraeus crypticus, including defence response, gut microbiome, and antibiotic resistance genes (ARGs), were studied. The cytochrome P450 enzyme activity and reactive oxygen species levels increased, activating the defense response. The superoxide dismutase and glutathione S-transferase activity, and the expression of immune defense molecules such as coelomic cytolytic factor, lysozyme, bactericidal protein fetidins and lysenin changed. Furthermore, the diversity of the gut microbiome decreased, and the relative abundance of Bacteroidetes decreased significantly at the phylum level but increased in pathogenic and antibiotic-secreting bacteria (Rhodococcus and Streptomyces) at the genus level. However, the soil microbiome was not significantly different from that of the control group. The relative abundance of ARGs in the gut and soil microbiome significantly increased with enrofloxacin concentration, and the fluoroquinolone ARGs were significantly increased in both the soil (20.85-fold, p < 0.001) and gut (11.72-fold, p < 0.001) microbiomes. Subtypes of ARGs showed a positive correlation with Rhodococcus, which might increase the risk of disease transmission and the probability of drug-resistant pathogens. Furthermore, mobile genetic elements significantly promote the spread of ARGs.

Synthesis and evaluation of dual-action kanglemycin-fluoroquinolone hybrid antibiotics.

Bacterial resistance threatens the utility of currently available antibiotics. Rifampicin, a cornerstone in the treatment of persistent Gram-positive infections, is prone to the development of resistance resulting from single point mutations in the antibiotic's target, RNA polymerase. One strategy to circumvent resistance is the use of 'hybrid' antibiotics consisting of two covalently linked antibiotic entities. These compounds generally have two distinct cellular targets, reducing the probability of resistance development and potentially providing simplified pharmacological properties compared to combination therapies using the individual antibiotics. Here we evaluate a series of semi-synthetic hybrid antibiotics formed by linking kanglemycin A (Kang A), a rifampicin analog, and a collection of fluoroquinolones. Kang A is a natural product antibiotic which contains a novel dimethyl succinic acid moiety that offers a new attachment point for the synthesis of hybrid antibiotics. We compare the activity of the Kang A hybrids generated via the acid attachment point to a series of hybrids linked at the compound's naphthoquinone ring system. Several hybrids exhibit activity against bacteria resistant to Kang A via the action of the partnered antibiotic, suggesting that the Kang scaffold may provide new avenues for generating antibiotics effective against drug-resistant infections.

Photodegradation of fluoroquinolones in aqueous solution under light conditions relevant to surface waters, toxicity assessment of photoproduct mixtures.

Photochemical degradation of fluoroquinolones ciprofloxacin, enrofloxacin and norfloxacin in aqueous solution under light conditions relevant to surface waters at neutral and alkaline pH was found to proceed readily with half-lives between 0.9 and 2.7 min. The products of photochemical degradation identified by HPLC-MS included defluorinated, hydroxylated, and decarboxylated structures as well as structures with opened cyclic structures. For all of the studied substances, the reaction pathways were influenced significantly by the pH of the reaction system, with more products formed at alkaline pH than at neutral pH: the ratios of products in neutral and alkaline pH were 16/26, 9/19, 15/23 for ciprofloxacin, enrofloxacin, and norfloxacin, respectively. The structures of photoproducts and pathways of photochemical degradation are proposed. The antibacterial activities of photoproduct mixtures tested on E. coli and S. epidermidis were significantly higher in comparison to parental antibiotics in the case of both ciprofloxacin and enrofloxacin with p-values less than 0.0001 in most cases. The effect of the photoproducts was shown to be dependent on the pH value of the original antibiotic solutions before photodegradation: for ciprofloxacin, antibacterial activity against E. coli was more notably pronounced with regard to neutral pH photoproducts, while a less significant, or in one case not significant, effect of pH was observed against S. epidermidis; for norfloxacin, antibacterial activity against both E. coli and S. epidermidis was especially high with regard to alkaline pH photoproducts.

Investigation of the effects of three different generations of fluoroquinolone derivatives on antioxidant and immunotoxic enzyme levels in different rat tissues.

Fluoroquinolones (FQs) are synthetic and broad-spectrum antimicrobial drugs derived from nalidixic acid. FQs are used against SARS-CoV-2 in our country, and for the treatment of some urinary tract diseases, gastrointestinal diseases, respiratory tract diseases, sexually transmitted diseases, and dermatological diseases. The present study investigated the effect of 1-,7-,14-day treatments of three different FQ derivatives; ciprofloxacin (CIP) 80 mg/kg/day, levofloxacin (LVX) 40 mg/kg/day, and moxifloxacin (MXF) 40 mg/kg/day, on biochemical parameters, lipid peroxidation, antioxidant enzymes, and immunotoxicity. 72 Wistar albino male rats were distributed to four groups including 18 rats in each group and were sacrificed on three different time points. The 14-day treatment of MXF significantly reduced the levels of aspartate aminotransferase (AST), glucose, reduced glutathione (GSH), malondialdehyde (MDA), catalase (CAT), myeloperoxidase (MPO), adenosine deaminase (ADA), and glutathione peroxidase (GPx). Furthermore, 14-day treatment of LVX increased liver [GSH, MPO, ADA, superoxide dismutase (SOD)], and GSH (erythrocyte) levels; whereas it significantly reduced the levels of AST, TG (triglycerides) and associated parameters levels in all the tissues (MDA), erythrocytes, and liver (MPO, CAT, SOD, GPx). After 14-day treatment of CIP; the erythrocyte levels of GSH, MPO, GPx, and CAT significantly decreased; whereas the levels of glucose, creatinine, MPO (liver), and GST (kidney and erythrocyte) significantly increased. It has been concluded that FQ derivatives used in this experiment did not display any correlation in terms of the efficacies in the different time points and tissues. Thus, it is recommended to use such FQ derivatives considering the duration of use and target tissue.

Delayed toxicity of three fluoroquinolones and their mixtures after neonatal or embryonic exposure, in Daphnia magna.

Fluoroquinolones (FQs) are antibacterial drugs, used both in human and veterinary medicine, that are currently considered as emerging micropollutants. This study investigated the delayed toxic effects of enrofloxacin (ENR), flumequine (FLU), levofloxacin (LEV) and their binary mixtures in D. magna. For this purpose, a 10-day follow-up in pure medium was added to the standard D. magna immobilization test. During this follow-up, phenotypic alterations were evidenced, which were related to scarce or zeroed egg production and early mortality. Consequently, the EC50 s recalculated at the end of the follow-up were always remarkably lower than those obtained after the 48 h immobilization test: ENR 3.13 vs. 16.72 mg L-1; FLU 7.18 vs. 25.35 mg L-1; LEV 15.11 vs. > 40 mg L-1. To analyse the possible interactions within the binary mixtures, the method of nonlinear additive isoboles was applied. The three compounds showed invariably to follow the principle of concentration addition. Furthermore, as previous experiments showed toxicity of FLU and ENR after embryonic exposure of D. magna at a concentration of 2 mg L-1, an additional two embryonic tests were conducted with identical design: one with 2 mg L-1 LEV and the other with a ternary mixture containing 0.66 mg L-1 of each of the three FQs. The embryos were exposed for three days in vitro to the drug solutions and were then reconducted to pure medium for 21 days observation. Both the tests ended-up with only non-significant effects on growth and reproduction, confirming the lower toxicity of LEV, when compared to ENR and FLU, and the absence of any evident synergistic interaction among the three FQs. Overall, these studies have shown two relevant features related to the toxicity of the three FQs: (1) they give rise to delayed toxic effects in D. magna that are undetectable by the standard immobilization test; (2) their interaction in mixtures follow the principle of Concentration Addition. Both these indications concern the Environmental Risk Assessment of FQs and may be of interest to regulatory authorities.