Ciprofloxacin Exposure Research Articles

Trace antibiotic exposure affects murine gut microbiota and metabolism

Gut microbiota is important for host metabolism regulation. Antibiotic exposure disturbs this regulation by affecting the microbiome. Trace levels of antibiotics in water have been widely reported and the impact on gut microbiota remains understudied. We provide evidence of trace antibiotic exposure affecting the host's gut microbiota using a mouse model exposed to trace amounts of azithromycin (AZI) or ciprofloxacin (CIP) in drinking water. AZI exposure in males changed the distribution of gram-positive (Firmicutes and Bacteroidetes) and gram-negative (Proteobacteria, Fusobacteria, and Verrucomicrobia) bacteria at an early age. Both AZI and CIP resulted in abnormal microbiota maturation. Additionally, the production of short-chain fatty acids (SCFAs), including acetate, butyrate, and propionate, in females is affected. Serum hormone and metabolome levels shifted after trace antibiotic exposure. AZI and CIP exposure broadly disrupted original host-microbe interaction relationships between the gut microbiota and SCFAs or serum metabolites. In this study, we demonstrated that trace antibiotic exposure was associated with extensive gut microbiota and metabolism perturbation in mice and that the potential health risks in susceptible populations should be considered.

Effects of Ciprofloxacin on the Production and Composition of Cellular Microcystins in Microcystis aeruginosa.

Antibiotics can affect the photosynthetic system of Microcystis, potentially altering the balance of carbon and nitrogen, which may influence the synthesis of different microcystin (MC) congeners. However, the regulatory mechanisms by which antibiotics affect the synthesis of various MC congeners in Microcystis remain unknown. In this study, the effects of ciprofloxacin (CIP) on the growth, carbon and nitrogen balance, amino acid composition, mcyB gene expression, and production of different MC congeners were investigated in two toxin-producing strains of Microcystis aeruginosa. The results show that CIP exposure significantly inhibited the growth of both strains, achieving an inhibition rate of 71.75% in FACHB-315 and 41.13% in FACHB-915 at 8 μg/L CIP by the end of the cultivation. The intracellular C:N ratio in FACHB-315 increased by 51.47%, while no significant change was observed in FACHB-915. The levels of leucine, tyrosine, and arginine, as identified and quantified by UPLC-MS/MS, were significantly altered at higher CIP concentrations, leading to a reduction in leucine percentage and a notable increase in tyrosine in both strains, which contributed to a reduction in MC-LR proportion and an increase in MC-RR and MC-YR proportion. Additionally, the expression of the mcyB gene was upregulated by as much as 5.57 times, indicating that antibiotic stress could enhance MC synthesis at the genetic level, contributing to the increased toxicity of cyanobacteria. These findings emphasize the significant role of CIP in the biochemical processes of M. aeruginosa, particularly in MC synthesis and composition, providing valuable insights into the ecological risks posed by antibiotics and harmful cyanobacteria.

Quinolone antibiotics stimulate bacterial mercury methylation by Geobacter metallireducens GS-15

Bacterial mercury (Hg) methylation is critical for bioremediating Hg pollution, but the impact of emerging antibiotics on this process has rarely been reported. This study innovatively investigated the interactions between Hg-methylating bacteria of Geobacter metallireducens GS-15 and two quinolone antibiotics: lomefloxacin (LOM) and ciprofloxacin (CIP) at 5 μg/L. Short-term LOM exposure increased methylmercury (MeHg) yield by 36 % compared to antibiotic-free conditions, caused by hormesis to alter bioactivities of single GS-15 cells. Long-term CIP exposure led to more antibiotic resistance and mercury tolerance in GS-15 cells, doubling MeHg productivity and significantly increasing expression of Hg methylation (hgcA by 95 folds) and antibiotic resistance (gyrA by 54 folds) genes, while mercury resistance gene merA only increased by 2.5 folds than without selective pressure. These results suggest quinolone antibiotics at environmentally contaminated concentrations stimulate bacterial Hg methylation to form highly toxic MeHg, raising considerable concern for the Hg-antibiotic complex in contaminated environments.

Association between maternal antibiotic exposure and emotional and behavioural problems in children at four years of age: A biomonitoring-based prospective study

BackgroundMaternal exposure to multiple antibiotics exposure during pregnancy has attracted extensive attention, but biomonitoring studies linking prenatal antibiotic exposure to emotional and behavioural problems in children are limited. MethodsA total of 2475 pregnant women from the Ma’anshan Birth Cohort were included, and the Strengths and Difficulties Questionnaire was completed when their children turned four years of age. The levels of 41 maternal urinary antibiotics and two metabolites were measured during the first, second and third trimesters. Generalized estimating equations and binary logistic regression models were applied to analyse the associations between maternal antibiotic exposure and emotional and behavioural problems in children and to determine the sensitive period, respectively. A quantile-based g-computation (QGC) approach was employed to examine the combined effects of multiple antibiotics on emotional and behavioural problems in children. ResultsOverall, florfenicol and preferred-as-veterinary antibiotic (PVA) exposure during pregnancy increased the risk of emotional problems in children, and ofloxacin exposure increased the risk of hyperactivity-inattention. Maternal exposure to trimethoprime, ciprofloxacin, florfenicol, other antibiotics and PVA exposure during the first trimester was positively associated with emotional problems in children. Second-trimester trimethoprime concentrations and third-trimester ciprofloxacin concentrations were positively associated with hyperactivity-inattention. Third-trimester veterinary antibiotic (VA) exposure was negatively associated with hyperactivity-inattention, and second-trimester VA and PVA exposure was negatively associated with peer problems. The QGC model revealed that mixed antibiotic exposure in the first trimester exacerbated the risk of childhood emotional problems (the contribution of ciprofloxacin is prominent), and mixed antibiotic exposure in the second trimester increased the risk of hyperactivity-inattention (the contribution of trimethoprime is prominent). ConclusionMaternal mixed antibiotic exposure during the first and second trimesters increases the risk of emotional problems and hyperactivity-inattention in children at four years of age.

Selective increase of antibiotic-resistant denitrifiers drives N2O production in ciprofloxacin-contaminated soils

Agricultural systems significantly contribute to global N2O emissions, which is intensified by excessive fertilization and antibiotic residues, attracting global concerns. However, the dynamics and pathways of antibiotics-induced soil N2O production coupled with microbial metabolism remain controversial. Here, we explored the pathways of N2O production in agricultural soils exposed to ciprofloxacin (CIP), and revealed the underlying mechanisms of CIP degradation and the associated microbial metabolisms using 15N-isotope labeling and molecular techniques. CIP exposure significantly increases the total soil N2O production rate. This is attributed to an unexpected shift from heterotrophic and autotrophic nitrification to denitrification and an increased abundance of denitrifiers Methylobacillus members under CIP exposure. The most striking strain M. flagellatus KT is further discovered to harbor N2O-producing genes but lacks a N2O-reducing gene, thereby stimulating denitrification-based N2O production. Moreover, this denitrifying strain is probably capable of utilizing the byproducts of CIP as carbon sources, evidenced by genes associated with CIP resistance and degradation. Molecular docking further shows that CIP is well ordered in the catalytic active site of CotA laccase, thus affirming the potential for this strain to degrade CIP. These findings advance the mechanistic insights into N2O production within terrestrial ecosystems coupled with the organic contaminants degradation.

Salmonella Typhimurium alters galactitol metabolism under ciprofloxacin treatment to balance resistance and virulence.

Treatment of antibiotic resistance can significantly benefit from a deeper understanding of the interactions between drugs and genetics. The physiological responses and genetic mechanisms in antibiotic-exposed bacteria are not well understood. Traditional resistance studies, often retrospective, fail to capture the entire resistance development process and typically exhibit unpredictable dynamics. To explore how clinical isolates of S. Typhimurium respond to ciprofloxacin, we analyzed their adaptive responses. We found that S. Typhimurium RamA-mediated regulation disrupts microbial metabolism under ciprofloxacin exposure, affecting genes in the galactitol metabolic pathways. This disruption facilitates adaptive responses to drug therapy and enhances the efficiency of intracellular survival. A more comprehensive and integrated understanding of these physiological and genetic changes is crucial for improving treatment outcomes.

Single and mixture exposure to atrazine and ciprofloxacin on Clarias gariepinus antioxidant defense status, hepatic condition and immune response

Atrazine (ATRA) and ciprofloxacin (CPRO) are widely detected, persistent and co-existing aquatic pollutants. This study investigated effects of 14-day single and joint ATRA and CPRO exposure on juvenile Clarias gariepinus. Standard bioassay methods were used to determine responses of oxidative stress, hepatic condition, and immunological biomarkers on days 7 and 14. Seven groups were used: Control, CPROEC, CPROSubl, ATRAEC, ATRASubl, CPROEC+ATRAEC, and CPROSubl+ATRASubl. The test substances caused decreased activity of superoxide dismutase, catalase, and glutathione peroxidase. Lipid peroxidation was elevated, especially in CPRO-ATRA mixtures. Serum aminotransferases (ALT, and AST), and alkaline phosphatase activity increased significantly. Total protein, albumin, total immunoglobulin, and respiratory burst decreased significantly. Therefore, single and joint exposure to CPRO and ATRA poses adverse consequences on aquatic life.

Combining machine learning with high-content imaging to infer ciprofloxacin susceptibility in isolates of Salmonella Typhimurium

Antimicrobial resistance (AMR) is a growing public health crisis that requires innovative solutions. Current susceptibility testing approaches limit our ability to rapidly distinguish between antimicrobial-susceptible and -resistant organisms. Salmonella Typhimurium (S. Typhimurium) is an enteric pathogen responsible for severe gastrointestinal illness and invasive disease. Despite widespread resistance, ciprofloxacin remains a common treatment for Salmonella infections, particularly in lower-resource settings, where the drug is given empirically. Here, we exploit high-content imaging to generate deep phenotyping of S. Typhimurium isolates longitudinally exposed to increasing concentrations of ciprofloxacin. We apply machine learning algorithms to the imaging data and demonstrate that individual isolates display distinct growth and morphological characteristics that cluster by time point and susceptibility to ciprofloxacin, which occur independently of ciprofloxacin exposure. Using a further set of S. Typhimurium clinical isolates, we find that machine learning classifiers can accurately predict ciprofloxacin susceptibility without exposure to it or any prior knowledge of resistance phenotype. These results demonstrate the principle of using high-content imaging with machine learning algorithms to predict drug susceptibility of clinical bacterial isolates. This technique may be an important tool in understanding the morphological impact of antimicrobials on the bacterial cell to identify drugs with new modes of action.

Effects of ciprofloxacin and levofloxacin on initial colonization of intestinal microbiota in Bufo gargarizans at embryonic stages

Ciprofloxacin (CIP) and levofloxacin (LEV) are broad-spectrum antibiotics with potent antibacterial activity. Although many studies have shown that antibiotics can lead to gut microbiota disruption, the effects of CIP and LEV on gut microbial colonization at the embryonic stage remain poorly characterized. Here, we evaluated the response of Bufo gargarizans embryos in terms of gut microbiota colonization, growth and developmental stages to CIP and LEV exposure. Embryos treated with 100 μg/L CIP and LEV exhibited significantly reduced diversity and richness of the gut microbiota, as well as altered community structure. Both CIP and LEV treatments resulted in an increase in the pathogenic bacteria Bosea and Aeromonas, and they appeared to be more resistant to CIP than LEV. Additionally, CIP exposure caused reduced total length and delayed the development in B. gargarizans embryos, while LEV increased the total length and promoted embryonic development. The present study revealed the adverse effects of CIP and LEV exposure on host gut microbiota, growth and development during the embryonic stage, and contributed new perspectives to the evaluation of early aquatic ecological risk under CIP and LEV exposure.

How denitrifiers defense ciprofloxacin: Insights from intracellular and extracellular stress response

Overuse of antibiotics has led to their existence in nitrogen-containing water. The impacts of antibiotics on bio-denitrification and the metabolic response of denitrifiers to antibiotics are unclear. We systematically analyzed the effect of ciprofloxacin (CIP) on bio-denitrification and found that 5 mg/L CIP greatly inhibited denitrification with a model denitrifier (Paracoccus denitrificans). Nitrate reduction decreased by 32.89 % and nitrous oxide emission increased by 75.53 %. The balance analysis of carbon and nitrogen metabolism during denitrification showed that CIP exposure blocked electron transfer and reduced the flow of substrate metabolism used for denitrification. Proteomics results showed that CIP exposure induced denitrifiers to use the pentose phosphate pathway more for substrate metabolism. This caused a substrate preference to generate NADPH to prevent cellular damage rather than NADH for denitrification. Notably, despite denitrifiers having antioxidant defenses, they could not completely prevent oxidative damage caused by CIP exposure. The effect of CIP exposure on denitrifiers after removal of extracellular polymeric substances (EPS) demonstrated that EPS around denitrifiers formed a barrier against CIP. Fluorescence and infrared spectroscopy revealed that the binding effect of proteins in EPS to CIP prevented damage. This study shows that denitrifiers resist antibiotic stress through different intracellular and extracellular defense strategies.

Bacterial dynamics of the plastisphere microbiome exposed to sub-lethal antibiotic pollution

BackgroundAntibiotics and microplastics are two major aquatic pollutants that have been associated to antibiotic resistance selection in the environment and are considered a risk to human health. However, little is known about the interaction of these pollutants at environmental concentrations and the response of the microbial communities in the plastisphere to sub-lethal antibiotic pollution. Here, we describe the bacterial dynamics underlying this response in surface water bacteria at the community, resistome and mobilome level using a combination of methods (next-generation sequencing and qPCR), sequencing targets (16S rRNA gene, pre-clinical and clinical class 1 integron cassettes and metagenomes), technologies (short and long read sequencing), and assembly approaches (non-assembled reads, genome assembly, bacteriophage and plasmid assembly).ResultsOur results show a shift in the microbial community response to antibiotics in the plastisphere microbiome compared to surface water communities and describe the bacterial subpopulations that respond differently to antibiotic and microplastic pollution. The plastisphere showed an increased tolerance to antibiotics and selected different antibiotic resistance bacteria (ARB) and antibiotic resistance genes (ARGs). Several metagenome assembled genomes (MAGs) derived from the antibiotic-exposed plastisphere contained ARGs, virulence factors, and genes involved in plasmid conjugation. These include Comamonas, Chryseobacterium, the opportunistic pathogen Stenotrophomonas maltophilia, and other MAGs belonging to genera that have been associated to human infections, such as Achromobacter. The abundance of the integron-associated ciprofloxacin resistance gene aac(6’)-Ib-cr increased under ciprofloxacin exposure in both freshwater microbial communities and in the plastisphere. Regarding the antibiotic mobilome, although no significant changes in ARG load in class 1 integrons and plasmids were observed in polluted samples, we identified three ARG-containing viral contigs that were integrated into MAGs as prophages.ConclusionsThis study illustrates how the selective nature of the plastisphere influences bacterial response to antibiotics at sub-lethal selective pressure. The microbial changes identified here help define the selective role of the plastisphere and its impact on the maintenance of environmental antibiotic resistance in combination with other anthropogenic pollutants. This research highlights the need to evaluate the impact of aquatic pollutants in environmental microbial communities using complex scenarios with combined stresses.3sW_WiGiki6wh61j1XWikeVideo

Transcriptomic and proteomic analysis of the virulence inducing effect of ciprofloxacin on enterohemorrhagic Escherichia coli.

Enterohemorrhagic E. coli (EHEC) is considered to be the most dangerous pathotype of E. coli, as it causes severe conditions such as hemorrhagic colitis (HC) and hemolytic uremic syndrome (HUS). Antibiotic treatment of EHEC infections is generally not recommended since it may promote the production of the Shiga toxin (Stx) and lead to worsened symptoms. This study explores how exposure to the fluoroquinolone ciprofloxacin reorganizes the transcriptome and proteome of EHEC O157:H7 strain EDL933, with special emphasis on virulence-associated factors. As expected, exposure to ciprofloxacin caused an extensive upregulation of SOS-response- and Stx-phage proteins, including Stx. A range of other virulence-associated factors were also upregulated, including many genes encoded by the LEE-pathogenicity island, the enterohemolysin gene (ehxA), as well as several genes and proteins involved in LPS production. However, a large proportion of the genes and proteins (17 and 8%, respectively) whose expression was upregulated upon ciprofloxacin exposure (17 and 8%, respectively) are not functionally assigned. This indicates a knowledge gap in our understanding of mechanisms involved in EHECs response to antibiotic-induced stress. Altogether, the results contribute to better understanding of how exposure to ciprofloxacin influences the virulome of EHEC and generates a knowledge base for further studies on how EHEC responds to antibiotic-induced stress. A deeper understanding on how EHEC responds to antibiotics will facilitate development of novel and safer treatments for EHEC infections.

Ciprofloxacin affects nutrient removal in manganese ore-based constructed wetlands: Adaptive responses of macrophytes and microbes

Ciprofloxacin (CIP) has received considerable attention in recent decades due to its high ecological risk. However, little is known about the potential response of macrophytes and microbes to varying levels of CIP exposure in constructed wetlands. Therefore, lab-scale manganese ore-based tidal flow constructed wetlands (MO-TFCWs) were operated to evaluate the responses of macrophytes and microbes to CIP over the long term. The results indicated that total nitrogen removal improved from 79.93% to 87.06% as CIP rose from 0 to 4 mg L−1. The chlorophyll content and antioxidant enzyme activities in macrophytes were enhanced under CIP exposure, but plant growth was not inhibited. Importantly, CIP exposure caused a marked evolution of the substrate microbial community, with increased microbial diversity, expanded niche breadth and enhanced cooperation among the top 50 genera, compared to the control (no CIP). Co-occurrence network also indicated that microorganisms may be more inclined to co-operate than compete. The abundance of the keystone bacterium (involved in nitrogen transformation) norank_f__A0839 increased from 0.746% to 3.405%. The null model revealed drift processes (83.33%) dominated the community assembly with no CIP and 4 mg L−1 CIP. Functional predictions indicated that microbial carbon metabolism, electron transfer and ATP metabolism activities were enhanced under prolonged CIP exposure, which may contribute to nitrogen removal. This study provides valuable insights that will help achieve stable nitrogen removal from wastewater containing antibiotic in MO-TFCWs.

Pooled Population Pharmacokinetic Analysis and Dose Recommendations for Ciprofloxacin in Intensive Care Unit Patients with Obesity.

Recent studies have explored the influence of obesity and critical illness on ciprofloxacin pharmacokinetics. However, variation across the subpopulation of individuals with obesity admitted to the intensive care unit (ICU) with varying renal function remains unexamined. This study aims to characterize ciprofloxacin pharmacokinetics in ICU patients with obesity and provide dose recommendations for this special population. Individual patient data of 34 ICU patients with obesity (BMI >30 kg/m2) from four studies evaluating ciprofloxacin pharmacokinetics in ICU patients were pooled and combined with data from a study involving 10 individuals with obesity undergoing bariatric surgery. All samples were collected after intravenous administration. Non-linear mixed effects modeling and simulation were used to develop a population pharmacokinetic model and describe ciprofloxacin exposure in plasma. Model-based dose evaluations were performed using a pharmacokinetic/pharmacodynamic target of AUC/MIC >125. The data from patients with BMI ranging from 30.2 to 58.1 were best described by a two-compartment model with first-order elimination and a proportional error model. The inclusion of Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) as a covariate on clearance reduced inter-individual variability from 57.3% to 38.5% (P <.001). Neither body weight nor ICU admission significantly influenced clearance or volume of distribution. Renal function is a viable predictor for ciprofloxacin clearance in ICU patients with obesity, while critical illness and body weight do not significantly alter clearance. As such, body weight and critical illness do not need to be accounted for when dosing ciprofloxacin in ICU patients with obesity. Individuals with CKD-EPI >60 mL/min/1.73 m2 may require higher dosages for the treatment of pathogens with minimal inhibitory concentration ≥0.25 mg/L.

Synthetic and natural rubber associated chemicals drive functional and structural changes as well as adaptations to antibiotics in in vitro marine microbiomes

The leaching of additives from plastics and elastomers (rubbers) has raised concerns due to their potential negative impacts on the environment and the development of antibiotic resistance. In this study, we investigated the effects of chemicals extracted from two types of rubber on microbiomes derived from a benthic sea urchin and two pelagic fish species. Additionally, we examined whether bacterial communities preconditioned with rubber-associated chemicals displayed adaptations to antibiotics. At the highest tested concentrations of chemicals, we observed reduced maximum growth rates and yields, prolonged lag phases, and increased alpha diversity. While the effects on alpha and beta diversity were not always conclusive, several bacterial genera were significantly influenced by chemicals from the two rubber sources. Subsequent exposure of sea urchin microbiomes preconditioned with rubber chemicals to the antibiotic ciprofloxacin resulted in decreased maximum growth rates. This indicates a more sensitive microbiome to ciprofloxacin when preconditioned with rubber chemicals. Although no significant interaction effects between rubber chemicals and ciprofloxacin exposure were observed in bacterial alpha and beta diversity, we observed log-fold changes in two bacterial genera in response to ciprofloxacin exposure. These findings highlight the structural and functional alterations in microbiomes originating from various marine species when exposed to rubber-associated chemicals and underscore the potential risks posed to marine life.

Dynamic responses of Salmonella Typhimurium to re-exposure to sublethal ciprofloxacin.

This study was designed to evaluate the history-dependent behaviors of Salmonella Typhimurium re-exposed to sublethal levels of ciprofloxacin. The S. Typhimurium cells were pre-exposed to 0 (CON), 1/16 (LOW), 1/8 (MED), and 1/4 (HIGH) minimum inhibitory concentrations (MICs) of ciprofloxacin, followed by re-exposure to the same concentrations. The bacterial growth, postantibiotic effect (PAE), relative fitness, and swimming motility of treatments were evaluated in the absence of ciprofloxacin. The lag phase duration (LPD) was estimate to assess bacterial recovery under ciprofloxacin exposure. A disk diffusion assay was used to determine the cross-resistance and collateral sensitivity of CON, LOW, MED, and HIGH treatments to ciprofloxacin (CIP), ceftriaxone (CEF), erythromycin (ERY), gentamicin (GEN), and polymyxin B (POL). The S. Typhimurium cells pre-exposed to ciprofloxacin were susceptible in antibiotic-free media, showing delayed growth. The highest PAE (>1h) and bacterial fluctuation (CV=5%) were observed at the High treatment compared to the CON. The HIGH treatment had the lowest relative fitness levels (0.87) and swimming motility (55mm). The LPD was significantly decreased at the LOW treatment (1.8h) when re-exposed to 1/16×MIC of ciprofloxacin. The LOW, MED, and HIGH treatments showed the cross-resistance to POL and the collateral sensitivity to CEF, ERY, and GEN. The pre-exposure to ciprofloxacin could induce phenotypic diversity, corresponding to the history-dependent behaviors. These results provide important insights for the dynamic nature of bacterial populations when re-exposed to sublethal concentrations of antibiotics.

In vivo evolution of antimicrobial resistance in a biofilm model of Pseudomonas aeruginosa lung infection.

The evolution of antimicrobial resistance (AMR) in biofilms has been repeatedly studied by experimental evolution in vitro, but rarely in vivo. The complex microenvironment at the infection site imposes selective pressures on the bacterial biofilms, potentially influencing the development of AMR. We report here the development of AMR in an in vivo mouse model of Pseudomonas aeruginosa biofilm lung infection. The P. aeruginosa embedded in seaweed alginate beads underwent four successive lung infection passages with or without ciprofloxacin (CIP) exposure. The development of CIP resistance was assessed at each passage by population analysis of the bacterial populations recovered from the lungs of CIP-treated and control mice, with subsequent whole-genome sequencing of selected isolates. As inflammation plays a crucial role in shaping the microenvironment at the infection site, its impact was explored through the measurement of cytokine levels in the lung homogenate. A rapid development of AMR was observed starting from the second passage in the CIP-treated mice. Genetic analysis revealed mutations in nfxB, efflux pumps (mexZ), and two-component systems (parS) contribution to CIP resistance. The control group isolates exhibited mutations in the dipA gene, likely associated with biofilm dispersion. In the initial two passages, the CIP-treated group exhibited an elevated inflammatory response compared to the control group. This increase may potentially contribute to the release of mutagenic reactive oxygen species and the development of AMR. In conclusion, this study illustrates the complex relationship between infection, antibiotic treatment, and immune response.

Compatible co-administration of BioThrax® vaccine and ciprofloxacin—Results of a randomized open-label drug-vaccine interaction trial

The recommended treatment for post-exposure prophylaxis (PEP) following known/suspected exposure to Bacillus anthracis involves immunization with anthrax vaccine adsorbed (AVA, i.e., BioThrax® vaccine) and a course of antimicrobial therapy. A drug-vaccine interaction clinical trial was conducted to determine whether this combined treatment might modify antimicrobial exposure or vaccine immunogenicity.A Phase 2, randomized, open-label, multi-center trial involving 154 healthy adult participants was completed to evaluate the effect of AVA immunization (three doses administered subcutaneously (SC) at weeks 0, 2 and 4) on the pharmacokinetics (PK) of ciprofloxacin, as well as the effect of ciprofloxacin administration (500 mg po bid) on the immunogenicity of AVA. PK parameters were derived using noncompartmental analysis of ciprofloxacin serum concentrations. Immunogenicity was assessed using a toxin neutralizing antibody (TNA) assay resulting in 50 % neutralization factor (NF50) values. Safety was assessed via reports of adverse events (AEs), clinically significant changes in laboratory parameters and vital signs, and collection of solicited local and systemic reactogenicity reactions.Statistical analyses of the steady state (SS) and single dose PK parameters Cmax and AUC0-–12h indicated that the AVA PEP regimen did not significantly modify ciprofloxacin exposure. Comparison of the geometric mean TNA NF50 values between participants receiving AVA + ciprofloxacin and those receiving AVA alone showed that the combined treatment was non-inferior to AVA alone. The trial met all prospectively defined success criteria for the primary PK endpoint and for the secondary PK and immunogenicity endpoints. There were no deaths, SAEs or AEs leading to drug discontinuation or study withdrawal during the trial.Overall, concomitant administration of ciprofloxacin and AVA produced no significant changes in the PK profile of ciprofloxacin nor in the immunogenicity of AVA. Furthermore, this trial demonstrated that the co-administration of ciprofloxacin and AVA was well tolerated in healthy adult participants.

Antibiotic exposure associated with nighttime sleep duration and daytime sleepiness in newlyweds.

Few studies have explored the relationship between antibiotic exposure and sleep in newlyweds. We applied the actor-partner interdependence moderation model to estimate the relationships of antibiotic exposure with nighttime sleep duration (weekday, weekend, and average sleep durations) and daytime sleepiness in newlyweds. We found that 99.0% of the 2698 enrolled individuals were exposed to at least one antibiotic. Among the newlyweds, exposure to florfenicol (β, - 0.077; 95% confidence interval [CI], - 0.143, - 0.011), exposure to chloramphenicols (- 0.086 [- 0.160, - 0.011]), and exposure to veterinary antibiotics (VAs) (- 0.106 [- 0.201, - 0.010]) were negatively associated with weekday sleep duration. Florfenicol, chloramphenicols, and VAs were also inversely related to average sleep duration in the newlyweds. Ciprofloxacin and cyadox exposure was significantly associated with an increase of 0.264 (0.030, 0.497) and (0.375 [0.088, 0.663]) Epworth Sleepiness Scale (ESS) scores in the newlyweds, respectively. Gender moderated the actor-partner effects of erythromycin and tetracyclines on the newlyweds' weekday sleep duration and ESS scores. Overall, exposure to florfenicol, chloramphenicols, and VAs shortened weekday and average sleep durations of newlyweds. Exposure to ciprofloxacin and cyadox promoted daytime sleepiness. Gender moderated the actor-partner effects of specific antibiotics on the weekday sleep duration and ESS scores of the newlyweds.

Persistent ciprofloxacin exposure induced the transformation of Klebsiella pneumoniae small colony variant into mucous phenotype

IntroductionSmall colony variant (SCV) is a bacterial phenotype closely related to persistent and recurrent infections. SCVs are mutations that occur within bacterial populations, resulting in a change in bacterial morphology and the formation of small colonies. This morphological change may enhance bacterial resistance to antibiotics and contribute to persistent and recurrent infections.MethodsWe isolated Klebsiella pneumoniae (KPN) and its SCV from a child with recurrent respiratory tract infections. KPN and SCV were treated with subinhibitory concentrations of antibiotics. growth curves, serum resistance experiments, macrophage phagocytosis experiments and whole genome sequencing were used to characterize KPN and SCV.ResultsAfter treating KPN and SCV with subinhibitory concentrations of antibiotics, we found that ciprofloxacin induced the SCV transition to the mucoid phenotype. We found that the growth of mucoid Klebsiella pneumoniae was significantly slower than maternal strain and SCV though growth curves. Serum resistance experiments showed that mucoid strains had significantly higher serum resistance compared to maternal strain and SCV. Macrophage phagocytosis experiments revealed that SCV had significantly higher intracellular survival rates compared to maternal strain and mucoid strains. Differential gene analysis of three strains revealed that the mucoid strain contained DNA polymerase V subunit UmuC gene on the plasmid, while the SCV strain had an additional IcmK family IV secretion protein on its plasmid.DiscussionOur study showed the SCV of KPN changed to a mucoid colony when exposed to subinhibitory concentrations of ciprofloxacin. The higher resistance of serum of mucoid colonies was possibly related to the UmuC gene, while the increased intracellular survival of SCV may be related to the IcmK family type IV secretion proteins.