Ciprofloxacin Exposure Research Articles

Pregnancy outcomes following quinolone and fluoroquinolone exposure during pregnancy: A systematic review and meta-analysis

Objective: To investigate whether maternal exposure to quinolones, fluoroquinolones and specifically ciprofloxacin is associated with major malformations and other adverse pregnancy outcomes.Methods: MEDLINE/PubMed, Embase and Reprotox® databases were searched. Observational studies with an exposed and control group were included.Results: Analysis of 8 cohort and 2 case-control studies showed no significant increases in rates of major malformations for quinolone (OR, 1.04; 95% CI 0.89–1.21), fluoroquinolone (RR, 0.89; 95% CI 0.70–1.14) and ciprofloxacin exposure (RR, 0.72; 95% CI 0.43–1.19). For fluoroquinolones, live birth rate was significantly decreased (RD, −0.04; 95% CI −0.08 to −0.01) whereas elective termination rate (RD, 0.04; 95% CI 0.02–0.05) was significantly increased.Conclusions: Quinolone, fluoroquinolone and ciprofloxacin exposure were not associated with a significant increase in major malformations and adverse pregnancy outcomes, other than significantly decreased live birth rate and increased elective termination rate which may be the indicators of misperceived teratogenic risk.

Maternal antibiotic exposure and fetal outcomes: is there evidence for teratogenicity?

Aim: During pregnancy, untreated infections may be associated with low birth weight, preterm birth, and spontaneous abortion. Thus, use of antibiotics are commonly seen in pregnancy. In this study, we aimed to evaluate the possible teratogenic risks related to the maternally exposed antibiotics during pregnancy. Material and Methods: Data from pregnant women, who used antibiotics for several infectious diseases between 2014 and 2018, and admitted to our Teratology Information Service for drug analysis, were collected. Data concerning their medication, concomitant drugs and co-morbidities were documented. The possible teratogenic risks related to the drugs were evaluated. A follow-up was conducted with the women after delivery to obtain whether any major or minor congenital malformations occurred in the infants.Results: The maternal use of doxycycline between 3-6th weeks, and acyclovir between 1-2nd weeks of pregnancy resulted in elective termination. The maternal use of cefazoline between 3-4th weeks of pregnancy, and the use of amoxicillin-clavulanate between 3-6th weeks of gestation resulted in spontaneous abortion. In the outcome of one pregnancy, the concomitant exposure of miconazole, metronidazole, ciprofloxacin, ornidazole and isoconazole in the first two weeks of pregnancy resulted in hypothyroidism in the infant. Conclusions: Antibiotics presented no major teratogenic effects. However, their use in pregnancy should be used only when indicated. Pregnant women should have access to the information and specific advice on the use of medications with proven safety in pregnancy through counseling with the Teratology Information Services.

Physiologically-Based Pharmacokinetic model for Ciprofloxacin in children with complicated Urinary Tract Infection

In a recent multicenter population pharmacokinetic study of ciprofloxacin administered to children suffering from complicated urinary tract infection (cUTI), the apparent volume of distribution (V) and total plasma clearance (CL) were decreased by 83.6% and 41.5% respectively, compared to healthy children. To understand these differences, a physiologically-based pharmacokinetic model (PBPK) for ciprofloxacin was developed for cUTI children. First, a PBPK model in adults was developed, modified incorporating age-dependent functions and evaluated with paediatric data generated from a published model in healthy children. Then, the model was then adapted to a cUTI paediatric population according to the degree of renal impairment (KF) affecting renal clearance (CLRenal,) and CYP1A2 clearance (CLCYP1A2). Serum and urine samples obtained from 22 cUTI children were used for model evaluation. Lastly, a parameter sensitivity analysis identified the most influential parameters on V and CL. The PBPK model predicted the ciprofloxacin exposure in adults and children, capturing age-related pharmacokinetic changes. Plasma concentrations and fraction excreted unchanged in urine (fe) predictions improved in paediatric cUTI patients once CLrenal and CLCYP1A2 were corrected by KF. The presented PBPK model for ciprofloxacin demonstrates its adequacy to simulate different dosing scenarios to obtain PK predictions in a healthy population from 3 months old onwards. Model adaptation of CLRenal and CLCYP1A2 according to KF explained partially the differences seen in the plasma drug concentrations and fe vs time profiles between healthy and cUTI children. Nevertheless, it is necessary to further investigate the disease-related changes in cUTI to improve model predictions.

Ciprofloxacin Promoted qnrD Expression and Phylogenetic Analysis of qnrD Harboring Plasmids.

Morganella morganii SE10MM harboring quinolone resistance determinant qnrD was investigated in our study. An entirely sequenced novel 2,662 bp qnrD-plasmid pSE10MM was identified and deposited at GenBank under accession number KU160530. Nucleic acid sequence of pSE10MM showed 94-97% similarity to previously detected qnrD-plasmids of Proteus mirabilis strains. Phylogenetic analysis by Geneious 9.0.5 showed clusters of plasmids with possible common origin. Initial expression of qnrD gene was found 12.5 normalized to rpoB housekeeping gene. Subsequently, a sub-minimum inhibitory concentration (1 mg/L) ciprofloxacin exposure resulted in a fold change of 30.06 at 24 hours. In contrast, qnrD-plasmid pSE10MM copy number increased in time from 1.1 to 6.63. Chromosomal mutations of gyrA with S83I, gyrB with S463A, and parC with S80I amino acid substitutions were detected, but no other mutations have occurred as a consequence of ciprofloxacin exposure. Elevated expression of qnrD correlated with that of recA in M. morganii during ciprofloxacin exposure, which indicates SOS-dependent regulation of qnrD. Protective effect of QnrD plays a role in fluoroquinolone-resistant strain even in the presence of chromosomal mutations in gyrase and topoisomerase IV.

Population pharmacokinetic modeling to establish the role of P-glycoprotein on ciprofloxacin distribution to lung and prostate following intravenous and intratracheal administration to Wistar rats

Ciprofloxacin (CIP) is indicated for clinical treatment of urinary and respiratory tract infections. Poor infection site penetration and consequent insufficient exposure to the antimicrobial agent may be the reason for some therapeutic failures. Ciprofloxacin is reported as a substrate for efflux transporters, such as P-glycoprotein, which could be related to the presence of sub-therapeutic drug concentration at the infection site. In the present work we evaluated CIP pharmacokinetics (PK) in plasma and lung and prostate tissues of Wistar rats after intravenous (i.v.) and intratracheal (i.t.) dosing (7 mg/Kg) in the presence and absence of P-gp inhibitor tariquidar (TAR, 15 mg/Kg). Microdialysis was applied to determine free tissue concentration-time profiles and the obtained data were analyzed by non-compartmental and population PK (popPK) analysis. A sequential strategy was used to develop the popPK model: characterization of CIP PK in tissues (Tissue model) was performed subsequently to CIP PK modeling in plasma (Plasma model). Two and three compartmental models were used to simultaneously characterize plasma concentrations after i.t. and i.v. dosing; the distribution model was developed by separating the central compartment into venous and arterial compartment and by adding lung and prostate; TAR was identified as a significant covariate for clearance and volume of distribution of central compartment as well as for inter-compartmental clearance. Our results indicate an impact of P-gp on plasma PK, likely by acting on renal active secretion of CIP. Regarding CIP exposure in lung and prostate tissues, our results suggest a complex interplay between drug transporters; P-gp inhibition by TAR was likely counterbalanced by the activity of other efflux/influx transporters, which could not be fully characterized by our model.

Contribution of OqxAB Efflux Pump in Selection of Fluoroquinolone-Resistant Klebsiella pneumoniae.

The role of OqxAB efflux pump in Klebsiella pneumoniae was investigated in correlation with ciprofloxacin exposure. K. pneumoniae SE23 and K. pneumoniae SE191 were isolated from urinary tract infections and were analyzed in this study. Each carried oqxAB resistance determinant and exhibited ciprofloxacin MIC of 0.06 and 0.5 mg/L, respectively. Tested strains were initially exposed to their ciprofloxacin MIC values for 24 hours. Later on, the ciprofloxacin exposition has been increased to a daily 1, 2, 4, and to a final 8 mg/L. Total cellular RNA was extracted at 30, 60, 90, and 120 minutes of initial exposure and after every 24 hours. Quantitative reverse-transcriptase PCR was performed from each RNA sample. Mutation in gyrA and parC genes was analyzed in each strain and multilocus sequence typing (MLST) was performed. Ciprofloxacin exposure selected resistant strain from K. pneumoniae SE191; by contrast, K. pneumoniae SE23 was not adjustable to the increasing ciprofloxacin concentrations. During initial exposure, both oqxA and oqxB expression remained low (2−ΔCt = 1-2.03). However, increasing ciprofloxacin promoted oqxB expression as it reached fold increase of 15.8–22.8, while oqxA expression was maintained (2−ΔCt = 2-2.15). An amino acid substitution Ser83Tyr in gyrA was detected in K. pneumoniae SE191, but no additional mutations occurred as consequence to ciprofloxacin exposure. MLST identified K. pneumoniae SE191 as ST274, while K. pneumoniae SE23 belonged to the novel ST2567. Ciprofloxacin concentration-dependent upregulation of oqxAB efflux pump in K. pneumoniae is clonally related and contributes to selection for higher level of fluoroquinolone resistance.

RNA markers enable phenotypic test of antibiotic susceptibility in Neisseria gonorrhoeae after 10\u2009minutes of ciprofloxacin exposure

Antimicrobial-resistant Neisseria gonorrhoeae is an urgent public-health threat, with continued worldwide incidents of infection and rising resistance to antimicrobials. Traditional culture-based methods for antibiotic susceptibility testing are unacceptably slow (1–2 days), resulting in the use of broad-spectrum antibiotics and the further development and spread of resistance. Critically needed is a rapid antibiotic susceptibility test (AST) that can guide treatment at the point-of-care. Rapid phenotypic approaches using quantification of DNA have been demonstrated for fast-growing organisms (e.g. E. coli) but are challenging for slower-growing pathogens such as N. gonorrhoeae. Here, we investigate the potential of RNA signatures to provide phenotypic responses to antibiotics in N. gonorrhoeae that are faster and greater in magnitude compared with DNA. Using RNA sequencing, we identified antibiotic-responsive transcripts. Significant shifts (>4-fold change) in transcript levels occurred within 5 min of antibiotic exposure. We designed assays for responsive transcripts with the highest abundances and fold changes, and validated gene expression using digital PCR. Using the top two markers (porB and rpmB) we correctly determined the antibiotic susceptibility and resistance of 49 clinical isolates after 10 min exposure to ciprofloxacin. RNA signatures are therefore promising as an approach on which to build rapid AST devices for N. gonorrhoeae at the point-of-care, which is critical for disease management, surveillance, and antibiotic stewardship efforts.

Hot spots of antibiotic tolerant and resistant bacterial subpopulations in natural freshwater biofilm communities due to inevitable urban drainage system overflows

Antibiotic resistant bacteria are a threat to human life. Recently, sewers have been identified as potential reservoirs. The intermittent injection of sewage into adjacent surface waters is inevitable, due to capacity limitations of the urban drainage system. Information regarding the effect to natural freshwater biofilms (NFB) due to the intermittent contaminations are scarce. Therefore, a fundamental screening is necessary. In April, we placed NFB-attachment constructions in a brook upstream and downstream from urban drainage overflow constructions. In meanwhile two sampling campaigns were conducted. The sewage and the brook water were collected to gather information about antibiotic background exposure of ciprofloxacin (CIP), clarithromycin (CLA) and doxycycline (DOX). Six months later we experimentally determined the oxygen uptake rate (OUR) of the NFB-communities after a 24 h lasting exposure with additionally dosed antibiotics. Concentrations of 0.1, 1.0 and 10.0 mg L−1 were selected. CIP, CLA and DOX were individually dosed, and also in mixtures. The mean antibiotic background concentration in sewage was in a range of 575.5–1289.1 ng L−1, which mainly exceeded the concentrations published in literature. The determined mean concentration in the brook was in a range of 4.6–539.0 ng L−1. The first significant inhibition of the OUR with individually dosed antibiotics started mainly at a concentration of 1.0 mg L−1. Antibiotics in a mixture with concentrations of 0.1 and 1.0 mg L−1 were as effective as single dosed antibiotics with a concentration of 10.0 mg L−1. The increased antibiotic tolerance and resistance of NFB-communities downstream of the combined sewer overflow (CSO) structure was a consequence of a severe impact due to urban drainage overflows. Hence, NFB-communities downstream of CSO-constructions are hot spots of antibiotic tolerant and resistant subpopulations and access restrictions should be announced, if an infection risk is present.

Assessment of ecotoxicological effects of ciprofloxacin in Daphnia magna: life-history traits, biochemical and genotoxic effects.

Antibiotics (e.g. ciprofloxacin) have been detected in surface water and groundwater for several decades. In order to understand the potential impact of the continuous exposure of aquatic organisms to ciprofloxacin, a chronic assay was carried out with Daphnia magna. This approach allowed evaluation of the effects of ciprofloxacin on life-history and sub-individual parameters (antioxidant status and metabolic response: activities of catalase and glutathione S-transferases - GSTs; peroxidative damage; thiobarbituric acid reactive substances and genotoxic effects (genetic damage index, measured by the comet assay). Life-history parameters of D. magna showed no significant effects after ciprofloxacin exposure. Concerning oxidative stress and metabolism parameters, no significant alterations were reported for catalase and GSTs activities. However, a dual response was observed, with a significant decrease in lipid peroxidation levels at low ciprofloxacin concentrations (<0.013 mg/L), while a significant increase was verified at high ciprofloxacin concentrations (0.078 mg/L). The genotoxicity assay detected a significant increase in genetic damage index up to 0.013 mg/L of ciprofloxacin. The here-tested ciprofloxacin concentrations, which are ecologically relevant, did not cause significant impacts concerning the life-history parameters of D. magna; however, at the same levels of ciprofloxacin an oxidative stress and genotoxic damage scenarios were recorded.

Selective concentration for ciprofloxacin resistance in Escherichia coli grown in complex aquatic bacterial biofilms

There is concern that antibiotics in the environment can select for and enrich bacteria carrying acquired antibiotic resistance genes, thus increasing the potential of those genes to emerge in a clinical context. A critical question for understanding and managing such risks is what levels of antibiotics are needed to select for resistance in complex bacterial communities. Here, we address this question by examining the phenotypic and genotypic profiles of aquatic communities exposed to ciprofloxacin, also evaluating the within-species selection of resistant E. coli in complex communities. The taxonomic composition was significantly altered at ciprofloxacin exposure concentrations down to 1 μg/L. Shotgun metagenomic analysis indicated that mobile quinolone resistance determinants (qnrD, qnrS and qnrB) were enriched as a direct consequence of ciprofloxacin exposure from 1 μg/L or higher. Only at 5–10 μg/L resistant E.coli increased relative to their sensitive counterparts. These resistant E. coli predominantly harbored non-transferrable, chromosomal triple mutations (gyrA S83 L, D87N and parC S80I), which confer high-level resistance. In a controlled experimental setup such as this, we interpret effects on taxonomic composition and enrichment of mobile quinolone resistance genes as relevant indicators of risk. Hence, the lowest observed effect concentration for resistance selection in complex communities by ciprofloxacin was 1 μg/L and the corresponding no observed effect concentration 0.1 μg/L. These findings can be used to define and implement discharge or surface water limits to reduce risks for selection of antibiotic resistance in the environment.

Ciprofloxacin vs. temperature: Antibiotic toxicity in the free-floating liverwort Ricciocarpus natans from a climate change perspective

The physiological responses of the aquatic liverwort Ricciocarpus natans to ciprofloxacin (Cipro) exposure under different growth temperatures were investigated. Cipro appears to act as an inhibitor of mitochondrial Complex III by blocking the oxidation of quinol, resulting in the formation of hydrogen peroxide (H2O2). H2O2 accumulation upon Cipro exposure is responsible for decreased photosynthesis in plants. The amount of H2O2 in plants is kept under control by antioxidant enzymes, whose activities are central to the responses of plants to Cipro yet are influenced by temperature. Increased temperature favored Cipro uptake by plants as well as its deleterious effects on mitochondrial activity; however, it also favored the activity of antioxidant enzymes, thereby preventing the exacerbation of the deleterious effects of Cipro. The uptake of Cipro by plants appears to be largely a passive process, although some uptake must be driven by an energy-consuming process. Ricciocarpus natans should be considered for programs aimed at the reclamation of Cipro since this plant exhibits high Cipro-tolerance, the capacity for accumulation and increased uptake rates of the antibiotic with increasing temperatures (from 20 to 30 °C).

Factors associated with distal symmetric polyneuropathies in adult Zambians: A cross-sectional, observational study of the role of HIV, non-antiretroviral medication exposures, and nutrition

BackgroundNon-antiretroviral (ART) drug exposures and poor nutrition may be important modifiable risk factors for distal symmetric polyneuropathies (DSP) in sub-Saharan Africa. MethodsWe conducted a cross-sectional study of DSP prevalence and factors associated with DSP among clinic attendees in urban and rural Zambia. All participants underwent neurologist-performed examination. Laboratory investigations seeking comorbid risk factors for DSP were performed for DSP cases. ResultsWe identified 31/137 (22.6%) HIV+ and 21/177 (11.9%) HIV− DSP cases. DSP prevalence did not differ by urbanicity, although rural participants were significantly more likely to have one asymptomatic DSP sign. Low dietary diversity, history of syphilis, history of tuberculosis, and prior metronidazole and ciprofloxacin use were associated with DSP amongst HIV+ cases, while age and education were associated with DSP in HIV− participants (all p-values < 0·05). In a multivariate logistic regression model, HIV (p = 0·0001) and age (p < 0·0001), and ciprofloxacin exposure (p = 0·01) remained independently associated with DSP. While diabetes was rare, supoptimal micronutrients levels were common among DSP cases regardless of HIV status. ConclusionsWhile HIV infection is strongly associated with DSP in Zambia, history of non-ART drug exposures and low dietary diversity are also important determinants of DSP in HIV+ individuals. Treatable micronutrient deficiencies were common.

Intraspecific variability of ciprofloxacin accumulation, tolerance, and metabolism in Chinese flowering cabbage (Brassica parachinensis)

To investigate the mechanism of genotype differences in ciprofloxacin (CIP) accumulation, this study was designed to compare the tolerance and metabolic responses to CIP exposure between low (Cutai) and high (Sijiu) CIP-accumulation cultivars of Brassica parachinensis. Decreases in biomass and chlorophyll content were significantly greater (p < 0.05) and toxicities were more severe within cell ultrastructures of Cutai compared to Sijiu. A sequential growth test also revealed that Sijiu was more tolerant to CIP stress compared to Cutai. Meanwhile, significantly higher (p < 0.05) root parameters and higher areas of the stele and xylem may be responsible for the increased uptake and transport of CIP in Sijiu. Ultra performance liquid chromatography-electrospray ionization tandem mass spectrometry (UPLC–ESI-MS/MS) analysis revealed that CIP was metabolized to three major metabolites by the hydroxylation and breakdown of the piperazinyl substituent in the CIP molecule. The enhanced metabolic transformation of CIP in Sijiu indicated a more efficient capacity to detoxify, which in turn favored an increased accumulation of CIP in this cultivar. Thus, the present study demonstrated that the stronger tolerance and metabolism of Sijiu to CIP were responsible for its high CIP accumulation, suggesting an evolutionary mechanism for adaptation to environmental stress.

The role of sulfides in stress-induced changes of Eh in Escherichia coli cultures

Real-time monitoring of the state of bacterial cultures is important in both experiment and biotechnology. Using Eh and sulfide sensors, we demonstrated that the abrupt reversible reduction in Eh (Eh jump), occurring during transition of E. coli from exponential growth to starvation and antibiotic-induced stresses, is the result of sulfide excretion from the cells. Changes in the potential of sensors had a two-phase mode. The potential reduced within 10–15min and returned within 10–30min. In the parental strain, maximum amplitudes of Eh jumps (ΔEh) were 25±2mV, 57±6mV and 36±7mV under isoleucine starvation, glucose depletion and ciprofloxacin exposure that corresponded to 43±3nM, 96±5nM and 140±1nM of sulfide, respectively. In the glutathione-deficient mutant (ΔgshA), ΔEh values and sulfide concentration increased 1.5–4 times compared to the parent. Stress-induced sulfide excretion occurred in the background of inhibition of growth and respiration and a decrease in the membrane potential. The formation of sulfide caused by cysteine desulfurization may be related with maintaining of cysteine homeostasis under conditions of slow metabolism. There was a close relationship between transmembrane fluxes of sulfide, cysteine and glutathione.

Antibiotic-induced release of small extracellular vesicles (exosomes) with surface-associated DNA

Recently, biological roles of extracellular vesicles (which include among others exosomes, microvesicles and apoptotic bodies) have attracted substantial attention in various fields of biomedicine. Here we investigated the impact of sustained exposure of cells to the fluoroquinolone antibiotic ciprofloxacin on the released extracellular vesicles. Ciprofloxacin is widely used in humans against bacterial infections as well as in cell cultures against Mycoplasma contamination. However, ciprofloxacin is an inducer of oxidative stress and mitochondrial dysfunction of mammalian cells. Unexpectedly, here we found that ciprofloxacin induced the release of both DNA (mitochondrial and chromosomal sequences) and DNA-binding proteins on the exofacial surfaces of small extracellular vesicles referred to in this paper as exosomes. Furthermore, a label-free optical biosensor analysis revealed DNA-dependent binding of exosomes to fibronectin. DNA release on the surface of exosomes was not affected any further by cellular activation or apoptosis induction. Our results reveal for the first time that prolonged low-dose ciprofloxacin exposure leads to the release of DNA associated with the external surface of exosomes.

Effect of ciprofloxacin on biological nitrogen and phosphorus removal from wastewater

In this work, both short-term and long-term experiments were therefore conducted to assess the effects of ciprofloxacin (0.2 and 2mg·L−1) on wastewater nutrient removal. The results showed that both levels of ciprofloxacin had no acute and chronic adverse effects on the surface integrity and viability of activated sludge. Short-term exposure to all the ciprofloxacin levels induced negligible influences on wastewater nutrient removal. However, the prolonged exposure to ciprofloxacin decreased total phosphorus and nitrogen removal efficiencies from 96.8, 95.8% (control) to 91.7, 84.9% (0.2mg·L−1) and 90.5%, 80.2% (2mg·L−1), respectively. The mechanism study showed that ciprofloxacin exposure suppressed denitrification and phosphorus uptake processes. It was also found that ciprofloxacin affected the transformations of intracellular polyhydroxyalkanoates and glycogen in the oxic and anoxic stages. Moreover the activities of nitrite reductase and polyphosphate kinase were inhibited by the presence of ciprofloxacin. Further analysis with high-throughput sequencing revealed that compared with the control, the abundances of polyphosphate accumulating organisms, glycogen accumulating organisms and denitrifying bacteria in ciprofloxacin exposure reactors reduced, which were consistent with the decreased nutrient removal performance measured in these reactors.

Population Pharmacokinetic Modeling as a Tool To Characterize the Decrease in Ciprofloxacin Free Interstitial Levels Caused by Pseudomonas aeruginosa Biofilm Lung Infection in Wistar Rats.

Biofilm formation plays an important role in the persistence of pulmonary infections, for example, in cystic fibrosis patients. So far, little is known about the antimicrobial lung disposition in biofilm-associated pneumonia. This study aimed to evaluate, by microdialysis, ciprofloxacin (CIP) penetration into the lungs of healthy and Pseudomonas aeruginosa biofilm-infected rats and to develop a comprehensive model to describe the CIP disposition under both conditions. P. aeruginosa was immobilized into alginate beads and intratracheally inoculated 14 days before CIP administration (20 mg/kg of body weight). Plasma and microdialysate were sampled from different animal groups, and the observations were evaluated by noncompartmental analysis (NCA) and population pharmacokinetic (popPK) analysis. The final model that successfully described all data consisted of an arterial and a venous central compartment and two peripheral distribution compartments, and the disposition in the lung was modeled as a two-compartment model structure linked to the venous compartment. Plasma clearance was approximately 32% lower in infected animals, leading to a significantly higher level of plasma CIP exposure (area under the concentration-time curve from time zero to infinity, 27.3 ± 12.1 μg · h/ml and 13.3 ± 3.5 μg · h/ml in infected and healthy rats, respectively). Despite the plasma exposure, infected animals showed a four times lower tissue concentration/plasma concentration ratio (lung penetration factor = 0.44 and 1.69 in infected and healthy rats, respectively), and lung clearance (CLlung) was added to the model for these animals (CLlung = 0.643 liters/h/kg) to explain the lower tissue concentrations. Our results indicate that P. aeruginosa biofilm infection reduces the CIP free interstitial lung concentrations and increases plasma exposure, suggesting that plasma concentrations alone are not a good surrogate of lung concentrations.

Exposure to sub-inhibitory concentrations of gentamicin, ciprofloxacin and cefotaxime induces multidrug resistance and reactive oxygen species generation in meticillin-sensitive Staphylococcus aureus.

The role of antibiotics below their MIC in the development of bacterial drug resistance is becoming increasingly important. We investigated the effect of sub-MICs of bactericidal antibiotics on the susceptibility pattern of Staphylococcus aureus and evaluated the role of free radicals. A total of 12 S. aureus strains were recovered from pus samples and their antibiograms determined. The test isolates were treated with sub-MIC levels of tetracycline, gentamicin, ciprofloxacin and cefotaxime. Alterations in their respective breakpoints were observed along with measurements of free radical generation by nitro blue tetrazolium test.Results/Key findings. Gentamicin, ciprofloxacin and cefotaxime exposure significantly altered the breakpoints of exposed isolates against several tested antibiotics and higher levels of free radicals were generated after antibiotic exposure. Our study demonstrates that sub-MIC levels of antimicrobials can lead to resistance and cross-resistance across several classes of antibiotics in wild strains of S. aureus, possibly by free radical production. The molecular mechanisms behind the acquisition of drug resistance at low antibiotic concentrations and the specific target genes of reactive oxygen speciesneed to be explored further.

Effect of subinhibitory concentrations of tigecycline and ciprofloxacin on the expression of biofilm-associated genes and biofilm structure of Staphylococcus epidermidis.

Staphylococcus epidermidis is a leading cause of foreign body-associated infections. This is related to the bacterium's ability to form biofilms on synthetic materials. Bacteria within a biofilm may be exposed to subinhibitory concentrations (sub-MICs) of antibiotics because of an agent's limited penetration into the biofilm core. Here, we investigated the effect of sub-MICs of tigecycline and ciprofloxacin on the expression of biofilm-associated genes, i.e. icaA, altE and sigB, and the biofilm structure of five clinical isolates of S. epidermidis. For most tested isolates, the expression of these genes increased after exposure to 0.25 MIC and 0.5 MIC tigecycline. A slight decrease in icaAmRNA levels was observed only in two isolates in the presence of 0.25 MIC tigecycline. The effect of ciprofloxacin exposure was isolate-dependent. At 0.5 MIC, ciprofloxacin induced an increase of sigB and icaAmRNA levels in three of the five tested isolates. At the same time, expression of the altE gene increased in all isolates (from 1.3-fold to 42-fold, depending on the strain). Confocal laser scanning microscopy analysis indicated that sub-MIC ciprofloxacin decreased biofilm formation, whereas tigecycline stimulated this process. Our data suggest that sub-MIC tigecycline may have bearing on the outcome of infections.

Intranasal delivery of ciprofloxacin to rats: A topical approach using a thermoreversible in situ gel

Intranasal administration of antibiotics is an alternative and attractive delivery approach in the treatment of local infections such as chronic rhinosinusitis. This topical route has the advantage of delivering high drug concentrations directly to the site of infection when trying to eradicate the highly resistant bacterial biofilms. The purpose of this study was to assess and compare the pharmacokinetic parameters of ciprofloxacin following intranasal and intravenous administrations to rats in plasma, olfactory bulb and nasal mucosa of two different nasal regions. For intranasal administration a thermoreversible in situ gel was used to increase drug residence time in nasal cavity. Ciprofloxacin concentration time-profile in nasal mucosa of the studied anterior region (at naso- and maxilloturbinates level) was markedly higher after intranasal administration (0.24mg/kg) than that following intravenous administration (10mg/kg), while in nasal mucosa of the more posterior region (at ethmoidal turbinates level) ciprofloxacin concentrations were found to be higher after intranasal administration when the different dose administered by both routes is taken into account. A plateau in ciprofloxacin concentration was observed in nasal mucosa of both studied regions after intranasal administration, suggesting a slow delivery of the drug over a period of time using the nasal gel formulation. In plasma and olfactory bulb, concentration of ciprofloxacin was residual after intranasal administration, which demonstrates this is a safe administration route by preventing systemic and particularly central nervous system adverse effects. Dose-normalized pharmacokinetic parameters of ciprofloxacin exposure to nasal mucosa revealed higher values after intranasal delivery not only in the anterior region but also in the posterior nasal region. In conclusion, topical intranasal administration appears to be advantageous for delivering ciprofloxacin to the biophase, with negligible systemic and brain exposure using a 41.7-fold lower dose than intravenous administration. Therefore, it may represent a promising approach in the drug management of chronic rhinosinusitis.