Co-administration Of Ciprofloxacin Research Articles

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.

Effect of diclofenac on the pharmacokinetics of ciprofloxacin in quail

This study investigated the Pharmacokinetics of ciprofloxacin alone or with diclofenac sodium in adult Japanese quails. The quails divided into two groups, the first group was dosed intraperitoneally with 50 mg/kg of ciprofloxacin, the second group was injected by 50 mg/kg of ciprofloxacin intraperitoneally then directly injected intraperitoneally by diclofenac sodium at a dosage of 5 mg/kg. Plasma concentrations of ciprofloxacin were determined by the spectrophotometer at wavelength 290 nm. Co-admiration of ciprofloxacin with diclofenac lead to appearing ciprofloxacin in plasma at 12.02, 6.4, 5.3, 3.30, 1.36, 0.60 μg/ml in the periods of 0.25, 0.50, 1, 2, 4 and 8 hours post-injection. A significantly increased in the concentration of ciprofloxacin at times of 0.25, 0.50, 1, and 2 hours post-injection and appeared at a concentration of 6.96, 3.09, 2.2, and 0.72 μg/ml. The pharmacokinetics of ciprofloxacin when given with diclofenac sodium was represented by 91% decrease in elimination constant rate, 53% decrease in elimination half-life t1/2, 64% decrease in volume of distribution to steady-state, 22% decrease in clearance, 28% increase area under curve, 41% decrease in area under moment curve, 53% decrease in mean residence time and 37% increase in maximum plasma concentration. Our study concludes that co-administration of ciprofloxacin with diclofenac sodium lead to alteration in some pharmacokinetic data of ciprofloxacin like effect on the plasma concentration and volume of distribution and clearance. This effect must be considered when therapy by ciprofloxacin with diclofenac, the co-administration of diclofenac with ciprofloxacin decrease the elimination of ciprofloxacin

Coadministration of tizanidine and ciprofloxacin: a retrospective analysis of the WHO pharmacovigilance database

PurposeTizanidine, an alpha-adrenergic substance with antinociceptive and antihypertensive effects, is extensively metabolized via cytochrome P450 (CYP) 1A2. Therefore, coadministration with potent CYP1A2 inhibitors, such as ciprofloxacin, is contraindicated. However, both drugs are broadly utilized in various countries. Their concomitant use bears an inherent high risk for clinically significant symptoms, especially in multimorbid patients experiencing polypharmacy. This study aims to investigate the impact of coadministration of tizanidine and ciprofloxacin using real-world pharmacovigilance data and to raise awareness of this potentially underestimated safety issue.MethodsWe conducted a retrospective study including Individual Case Safety Reports (ICSR) registered until March 1, 2017, in the World Health Organization (WHO) global database. Demographic data, drug administration information, the course of the adverse drug reaction (ADR), its severity, and outcomes were analyzed for cases reporting ciprofloxacin comedication.ResultsIn 91 (2.0%) of the identified 4192 worldwide ICSR on tizanidine, coadministration of ciprofloxacin was reported. Most of the patients were female (n = 59, 64.8%) with a median age of 54 years (range 13–85 years). The countries contributing most reports were the USA (n = 54, 59.3%) and Switzerland (n = 16, 17.6%). ADRs reported most often affected the nervous system and the cardiac function, especially with large tizanidine doses or drugs with CNS and cardiovascular depressant effects. In two cases, a fatal outcome was reported.ConclusionDespite the existing formal contraindication, the concomitant use of tizanidine and ciprofloxacin can be observed in real-world clinical practice. Reactions mainly affected the central nervous and the cardiovascular system resulting in potentially severe adverse effects. The concomitant use of tizanidine and ciprofloxacin should absolutely be avoided.

Establishment of a drug-induced rhabdomyolysis mouse model by co-administration of ciprofloxacin and atorvastatin

Rhabdomyolysis is one of the serious side effects of ciprofloxacin (CPFX), a widely used antibacterial drug; and occasionally, acute kidney injury (AKI) occurs. Often, rhabdomyolysis has occurred in patients taking CPFX co-administered with statins. The purpose of this study is to establish a mouse model of drug-induced rhabdomyolysis by co-administration of CPFX and atorvastatin (ATV) and to clarify the mechanisms of its pathogenesis. C57BL/6J mice treated with L-buthionine-(S,R)-sulfoximine (BSO), a glutathione synthesis inhibitor, were orally administered with CPFX and ATV for 4 days. Plasma levels of creatinine phosphokinase (CPK) and aspartate aminotransferase (AST) were significantly increased in the CPFX and ATV-co-administered group. Histopathological examination of skeletal muscle observed degeneration in gastrocnemius muscle and an increased number of the satellite cells. Expressions of skeletal muscle-specific microRNA and mRNA in plasma and skeletal muscle, respectively, were significantly increased. The area under the curve (AUC) of plasma CPFX was significantly increased in the CPFX and ATV-co-administered group. Furthermore, cytoplasmic vacuolization and a positively myoglobin-stained region in kidney tissue and high content of myoglobin in urine were observed. These results indicated that AKI was induced by myoglobin that leaked from skeletal muscle. The established mouse model in the present study would be useful for predicting potential rhabdomyolysis risks in preclinical drug development.

Co-administration of ginseng and ciprofloxacin ameliorates epididymo-orchitis induced alterations in sperm quality and spermatogenic cells apoptosis following infection in rats.

Korean red ginseng (KRG) may be a beneficial adjuvant along with ciprofloxacin to ameliorate devastating effects of epididymo-orchitis (EO) on male fertility. This study intends to assay the effects of KRG and ciprofloxacin on sperm quality and spermatogenic cells apoptosis in EO rats. We divided 54 adult rats into nine groups (n=6 rats per group): control (CO), sham-operated (SH), EO (E); ciprofloxacin (C), EO-ciprofloxacin (EC), KRG (G), EO-KRG (EG), ciprofloxacin-KRG (CG) and EO-ciprofloxacin-KRG (ECG). We administered ciprofloxacin and KRG 48hr after the Escherichia coli (E. coli) injection for 10days. Bilateral orchiectomy was performed after one sperm cycle (14days) following the last treatment with ciprofloxacin and KRG. Total and progressive motility of E, C and EC groups decreased. However, motility is improved in CG and ECG in comparison with these groups. The E group induced negative changes in the architecture of testes tissue and dramatic increase in apoptosis indices. Interestingly, co-administration of ciprofloxacin and KRG has dramatically improved Miller's and Johnsen's scores and decreased the apoptosis indices of animals in the ECG group. Combined treatment of ciprofloxacin and KRG may improve the quality of spermatozoa and attenuated apoptosis indices in the ECG group.

Inhibitory effect of ciprofloxacin on β‐glucuronidase‐mediated deconjugation of mycophenolic acid glucuronide

The interaction between mycophenolate (MPA) and quinolone antibiotics such as ciprofloxacin is considered to reduce the enterohepatic recycling of MPA, which is biotransformed in the intestine from MPA glucuronide (MPAG) conjugate excreted via the biliary system; however, the molecular mechanism underlying this biotransformation of MPA is still unclear. In this study, an in vitro system was established to evaluate β-glucuronidase-mediated deconjugation and to examine the influence of ciprofloxacin on the enzymatic deconjugation of MPAG and MPA resynthesis. Resynthesis of MPA via deconjugation of MPAG increased in a time-dependent manner from 5 to 60 min in the presence of β-glucuronidase. Ciprofloxacin and phenolphthalein-β-d-glucuronide (PhePG), a typical β-glucuronidase substrate, significantly decreased the production of MPA from MPAG in the β-glucuronidase-mediated deconjugation system. In addition, enoxacin significantly inhibited the production of MPA from MPAG, while levofloxacin and ofloxacin had no inhibitory effect on MPA synthesis. Pharmacokinetic analysis revealed that ciprofloxacin showed a dose-dependent inhibitory effect on MPA production from MPAG via β-glucuronidase with a half-maximal inhibitory concentration (IC50 ) value of 30.4 µm. While PhePG inhibited the β-glucuronidase-mediated production of MPA from MPAG in a competitive manner, ciprofloxacin inhibited MPA synthesis via noncompetitive inhibition. These findings suggest that the reduction in the serum MPA concentration during the co-administration of ciprofloxacin is at least in part due to the decreased enterohepatic circulation of MPA because of noncompetitive inhibition of deconjugation of MPAG by intestinal β-glucuronidase.

Use of Poly (ε-Lysine) Dendrons: A Strategy Targeting Bacterial Quorum Sensing and Biofilm Formation

Pseudomonas aeruginosa is recognised as a major aetiological agent of nosocomial infections, which are associated with multiple-antibiotic resistance. Among many of its important virulence factors is its ability to form biofilms on the surfaces of implantable medical devices and to produce toxic metabolites, pyocyanin, via an intercellular cell density-dependent signalling system of communication. In this study, poly (ε-lysine) dendrons composed of increasingly branching generations were synthesised, characterised, and examined for their effects on virulence factor production in P. aeruginosa. The results show that these hyperbranched poly (ε-lysine) dendrons, in particular the 3rd generation, can increase the efficacy of a conventional antibiotic, ciprofloxacin, and reduce pyocyanin production, with marginal effects on the rate of bacterial replication, suggesting that the observed effects are not due to dendron toxicity. Furthermore, dendron and ciprofloxacin coadministration was identified as the most effective strategy which highlights the potential of peptide-based dendrons as quorum sensing inhibitors.

Effect of artesunate on the dissolution profile and antimicrobial activity of ciprofloxacin hydrochloride

This study evaluated the in vitro physico-chemical implication of co-presentation of ciprofloxacin with artesunate. Thin layer chromatography (TLC) and ultraviolet (UV) analysis was used to monitor the co-presentation of the two drugs. The in vitro dissolution profile of ciprofloxacin hydrochloride tablet in the presence of artesunate tablet was evaluated in buffer with pH 1.2 and water at 37± 0.5°C as well as the effect artesunate on the antibacterial activity of ciprofloxacin. Physico-chemical interaction was not observed between ciprofloxacin and artesunate. However, a significant reduction in the dissolution rate of ciprofloxacin was observed in buffer pH 1.2 solution when compared with water as the medium (p 0.05). The results obtained in this study suggest that care should be taken during the co-administration of ciprofloxacin with the starting dose of artesunate. Key words: Ciprofloxacin, artesunate, physico-chemical interaction, dissolution rate,Staphylococcus aureus and Escherichia coli.

Effect of ciprofloxacin and grapefruit juice on oral pharmacokinetics of riluzole in Wistar rats

The objective of this study was to explore potential drug-drug/food interactions of ciprofloxacin and grapefruit juice, known hepatic cytochrome P450 (CYP) 1A2 inhibitors, on single-dose oral pharmacokinetics of riluzole, a substrate of CYP 1A2 enzymes. Pharmacokinetic parameters of riluzole were determined in Wistar rats after single-dose co-administration with ciprofloxacin and grapefruit juice. In-vitro metabolic inhibition studies using rat and human liver microsomes and intestinal absorption studies of riluzole in a rat everted gut-sac model were conducted to elucidate the mechanism of interaction. A validated HPLC method was employed to quantify riluzole in the samples obtained in various studies. Co-administration of ciprofloxacin with riluzole caused significant increase in systemic exposure of riluzole (area under the curve, maximum plasma concentration and mean residence time were found to increase). Co-administration of grapefruit juice with riluzole did not cause any significant difference in the pharmacokinetic parameters of riluzole. In-vitro metabolism studies demonstrated significant inhibition of riluzole metabolism when it was co-incubated with ciprofloxacin or grapefruit juice. No significant change was observed in apparent permeability of riluzole. Co-administration of ciprofloxacin with riluzole increases the systemic levels of riluzole and thereby the oral pharmacokinetic properties of riluzole while co-administration of grapefruit juice with riluzole has no significant effect.

Influence of Tacrolimus and Ciprofloxacin on Glucose Metabolism

Tacrolimus is an immunosuppressive drug that causes glucose intolerance. On the other hand, ciprofloxacin, which is widely used in the treatment of infectious diseases, is known to cause hypoglycemia as a side effect. We investigated the effects of tacrolimus and ciprofloxacin on serum glucose and insulin levels in rats, as well as on insulin secretion and the viability of HIT-T15 cells. The rats received intraperitoneal injections of tacrolimus and/or ciprofloxacin for 1 week, and their arterial blood was sampled after the administration of glucose. HIT-T15 cells were cultured in the presence of tacrolimus and/or ciprofloxacin, and the insulin level in the supernatant was measured. Ciprofloxacin did not show a significant effect on serum glucose and insulin levels after multiple administrations in the rats. In contrast, rats in the tacrolimus treatment group showed low serum insulin and high serum glucose levels. Moreover, the coadministration of ciprofloxacin and tacrolimus resulted in higher glucose levels compared with tacrolimus alone 0.5 h after glucose stimulation. In addition, we observed that the rats administered tacrolimus and/or ciprofloxacin had low body weight and food intake. Tacrolimus caused a dose-dependent decrease in the viability of the HIT-T15 cells. Furthermore, both drugs were highly toxic to HIT-T15 cells. In contrast, tacrolimus alone and coadministration of the drugs resulted in no significant difference in insulin secretion. These results suggest that the cytotoxic effects of ciprofloxacin and tacrolimus cause a decrease in insulin secretion, leading to glucose intolerance.

The effect of ciprofloxacin and clarithromycin on sildenafil oral bioavailability in human volunteers

Sildenafil is the first oral therapeutic agent for the management of male erectile dysfunction. Its oral bioavailability is only 40% due to extensive presystemic elimination, mainly by CYP3A4. This study examined the effect of coadministration of ciprofloxacin or clarithromycin, which inhibit CYP3A4, on the bioavailability and pharmacokinetics of sildenafil. Twelve healthy male volunteers received sildenafil alone or after pretreatment with the inhibitors in a balanced three-way crossover design. The pharmacokinetic analysis showed that ciprofloxacin coadministration with sildenafil significantly increased the AUC from 1407 +/- 380 to 2986 +/- 917 microg h/l (90% confidence interval 119%-159%) and the Cmax from 287 +/- 67 to 623 +/- 192 microg/l (90% confidence interval 127%-152%). Similarly, clarithromycin coadministration increased sildenafil AUC from 1407 +/- 380 to 3209 +/- 762 microg h/l (90% confidence interval 127%-161%) and Cmax from 287 +/- 67 to 694 +/- 259 microg/l (90% confidence interval 132%-157%). Ciprofloxacin coadministration and clarithromycin coadministration with sildenafil did not affect the rate of sildenafil absorption significantly. These results indicate that coadministration of ciprofloxacin and clarithromycin significantly increased sildenafil bioavailability which can be attributed to the inhibitory effect of ciprofloxacin and clarithromycin on CYP3A4. Dose adjustment of sildenafil is thus necessary when administered with such drugs.

THE EFFECT OF CIPROFLOXACIN AND CLARITHROMYCIN ON SILDENAFIL ORAL BIOAVAILABILITY IN HUMAN VOLUNTEERS

Sildenafil is the first oral therapeutic agent for the management of male erectile dysfunction. Its oral bioavailability is only 40% due to extensive presystemic elimination, mainly by CYP3A4. This study examined the effect of coadministration of ciprofloxacin or clarithromycin, which inhibit CYP3A4, on the bioavailability and pharmacokinetics of sildenafil. Twelve healthy male volunteers received sildenafil alone or after pretreatment with the inhibitors in a balanced three-way crossover design. The pharmacokinetic analysis showed that ciprofloxacin coadministration with sildenafil significantly increased the AUC from 1407 +/- 380 to 2986 +/- 917 microg h/l (90% confidence interval 119%-159%) and the Cmax from 287 +/- 67 to 623 +/- 192 microg/l (90% confidence interval 127%-152%). Similarly, clarithromycin coadministration increased sildenafil AUC from 1407 +/- 380 to 3209 +/- 762 microg h/l (90% confidence interval 127%-161%) and Cmax from 287 +/- 67 to 694 +/- 259 microg/l (90% confidence interval 132%-157%). Ciprofloxacin coadministration and clarithromycin coadministration with sildenafil did not affect the rate of sildenafil absorption significantly. These results indicate that coadministration of ciprofloxacin and clarithromycin significantly increased sildenafil bioavailability which can be attributed to the inhibitory effect of ciprofloxacin and clarithromycin on CYP3A4. Dose adjustment of sildenafil is thus necessary when administered with such drugs.

Neurotoxicodynamics of the interaction between ciprofloxacin and foscarnet in mice.

The potential for convulsions induced by the coadministration of ciprofloxacin (CPFX) and foscarnet (PFA) may be due not to a change in the distribution of CPFX to the brain but to a potential CPFX-induced inhibition of gamma-aminobutyric acid (GABA)-GABA(A) receptor binding in the presence of PFA.

Influence of ciprofloxacin on pharmacokinetics of rifampin

The pharmacokinetics of oral rifampin was studied in rabbits (24 mg/kg per day) as well as in humans (450 mg/d) who were taking antituberculosis medicine, after concurrent ciprofloxacin administration for a minimum of 5 days. There were no significant changes in the maximum plasma concentration (C max), time at C max, area under the plasma concentration-time curve, or elimination half-life of rifampin after ciprofloxacin coadministration in rabbits or humans.

Effect of Ciprofloxacin on the Pharmacokinetics of Multiple-Dose Phenytoin Serum Concentrations

We performed this study to determine if an interaction exists during the co-administration of ciprofloxacin with phenytoin. Seven healthy volunteers received oral phenytoin, 200 mg/day, as a single dose for 10 days. On day 9, phenytoin blood sampling was performed at times 0, 1, 2, 4, 6, 8, 10, 12, and 24 h. On day 10, oral ciprofloxacin, 500 mg, b.i.d. was initiated. On day 14, blood samples were collected as previously described. Pharmacokinetic analysis was performed to determine if there were differences between the area under the concentration time curve (AUC), maximum serum concentration, Cmax, and time of maximum serum concentration, Tmax, of phenytoin before and during co-administration of ciprofloxacin. Four subjects completed the study. Results of the analysis showed no significant differences between AUC, Cmax, and Tmax of phenytoin before and during ciprofloxacin administration. However, one subject showed marked reductions in both AUC and Cmax. Similar reductions in plasma concentrations have also been reported, resulting in breakthrough seizures. In conclusion, ciprofloxacin was not shown to increase phenytoin plasma concentrations or AUC in healthy volunteers. The potential for decreasing plasma phenytoin concentrations may exist and warrants close monitoring of levels when these two agents are given simultaneously.

Effects of enoxacin and ciprofloxacin on the theophylline metabolism in humans.

Some kinds of newer fluoroquinolone antibiotics are known to interact with theophylline, which is widely used as a potent bronchodilator in asthma or chronic obstructive lung disease. To evaluate the effect of enoxacin and ciprofloxacin on the metabolism of theophylline, aminophylline was administered intravenously in bolus (6 mg/kg) over 30 minutes to 6 healthy volunteers (age: year, body weight: , height: , female 3, male 3) before and after per oral 5-day medication of enoxacin and ciprofloxacin, respectively and we measured the level of theophylline in serum. The results were as follows: 1) Enoxacin and ciprofloxacin did not influence the volume of distribution significantly. 2) Enoxacin decreased the clearance of theophylline significantly (from to : p: p>0.005). 3) Enoxacin increased the elimination half life of theophylline significantly (from to : p: p>0.05). These results suggested that enoxacin influenced clearance and elimination half life significantly and thorough monitoring of the level of theophylline in patients with coadminstration of enoxacin and theophylline was necessary. In case of ciprofloxacin, the influence on the metabolism of theophylline was not statistically significant, but one exceptionally large decrease of the clearance and increase of the elimination halflife of theophylline suggested the necessity of monitoring of theophylline level during coadministration of ciprofloxacin and theophylline.

Fluoroquinolones and Theophylline Toxicity: Norfloxacin

To the Editor.— Many drugs, including the new broad-spectrum fluoroquinolone anti-infective agents, are known to interfere with theophylline metabolism by the hepatic cytochrome P450 system, causing toxic reactions to theophylline. Wijnands et al1reported increases in plasma theophylline concentrations during coadministration of enoxacin (110.9%) and to a lesser degree during coadministration of ciprofloxacin (22.8%) and pefloxacin (19.6%). Although two recent pharmacokinetic studies2,3suggest that a drug-drug interaction between norfloxacin and theophylline also exists, we are not aware of any case reports of elevated theophylline levels associated with this drug in the medical literature. Three cases have been reported to the Food and Drug Administration that suggest theophylline toxic effects in patients taking norfloxacin. Each patient had a baseline steady-state theophylline level that was increased by at least 50% after starting norfloxacin therapy. A judgment was made that concomitant drugs or diseases were not likely to be responsible. All