Biological properties of chitosan derivatives associated with the ceftazidime drug.

Chitosan has become promising as a biomaterial because of its biocompatible, biodegradable nature and non-toxic. The biochemical and antioxidant properties of chitosan modified with acetylacetone and ethylenediamine (Cacen) or diethylenetriamine (Cacdien) associated with ceftazidime (F) were investigated. Chitosan was characterized using Elemental Analysis (CHN), Thermal Analysis (TG/DTG/DSC), X-Ray Diffractometry (XRD), and was investigated an in vitro hemolytic cytotoxicity test, Artemia saline larvae for toxicity and in vitro antioxidant activity by DPPH (2,2-diphenyl-1-picrylhydrazyl). The chemical modification was confirmed by CHN, XRD and TG. The Cacen, Cacdien, CacenF and CacdienF derivatives presented high percentages of nitrogen (7.6%, 7.9%, 14.1% and 19.2%, respectively), confirming the modification and drug adsorption. The average molecular weight of chitosan and its derivatives were 132 kDa, with very few variations after modification. This incorporation decreased in the crystallinity index of Cacen (7.1%) and Cacdien (4.3%), as well as the incorporation of the drug (CacenF 0.3% and CacdienF 3.4%). FTIR spectra showed bands at 1580-1654 cm-1 referring to carbonyl and imine group and bands at 3500-3300 and 1462-1264 cm-1 related to vibration and deformation the amine group. 13C NMR spectroscopy was observed new peaks in carbonyl and imine regions (170-200 ppm). The thermal stability of the derivatives without the drug improved according to TG/DTG/DSC analysis, however there were decreased in the derivatives with the drug. The biocompatibility of the derivatives was confirmed by the low hemolytic rate (<5%), non-toxic on Artemia salina (LD50%>3000 ppm), and significant index (1-34%) of antioxidant activity. The results demonstrated that chitosan and its derivatives are promising biomaterials.

Investigation of the removal mechanism of antibiotic ceftazidime by green algae and subsequent microbic impact assessment.

The present study provides an integrated view of algal removal of the antibiotic ceftazidime and its basic parent structure 7-aminocephalosporanic acid (7-ACA), including contribution analysis, bacteriostatic and aquatic toxic assessment and metabolite verification. 92.70% and 96.07% of the two target compounds was removed after the algal treatment, respectively. The algal removal can be separated into three steps: a rapid adsorption, a slow cell wall-transmission and the final biodegradation. Additionally, while ceftazidime demonstrated an excellent inhibitory effect on Escherichia coli, there was no bacteriostasis introduced after the algal treatment, which could avoid favoring the harmful selective pressure. On the other hand, no significant aquatic impact of the two target compounds on rotifers was observed and it was not enhanced after the algal treatment. To better reveal the mechanism involved, metabolite analyses were performed. Δ-3 ceftazidime and trans-ceftazidime were regarded as the metabolites of ceftazidime and the metabolite of 7-ACA was regarded as a compound which shared the similar structure with 4-chlorocinnamic acid. Our study indicated that the green algae performed a satisfactory growth capacity and played a dominant role for the biodegradation of the target antibiotics, which achieved high removal efficiency and low environmental impact.

An integrated assessment of ceftazidime and photoproducts on the feeding behavior of rotifers: From exposure to post-exposure.

Compared to traditional toxicological studies, which depict the dose-effect of contaminants themselves on organisms at the given time, the exposure and post-exposure impacts of antibiotic ceftazidime and its photoproducts are carried out to systematically evaluate the environmental risk fate of ceftazidime in aquatic environments. For the exposure process, the promotion effect of ceftazidime on the feeding behavior of the rotifers decreased when the target compound was irradiated by sunlight, and the promotion effect was converted into inhibition effect, which indicated that the highest toxicity of ceftazidime on the feeding behavior of the rotifers was found after UV-B irradiation. The overcompensation occurred in the post-exposure, indicating a short - term effect of the corresponding photoproducts on the rotifer. In order to better understand the mechanism of this change, the photodegradation pathways of the target compound was analyzed and compared. The degradation degree under the UV-B irradiation had intensified greatly than that under the nature light irradiation. The reactive oxygen species (ROS) of the rotifer in exposure and post-exposure was also detected. Ceftazidime and photoproducts induced generation of ROS, indicating that oxidative damage occurred, and the decreasing of ROS levels could be viewed as the recovery of the rotifers in the post-exposure.

Antibiotics and renal branching morphogenesis: comparison of toxicities.

BACKGROUND: Many premature born neonates receive antibiotic drugs to treat infections, which are applied during active nephrogenesis. We studied the impact of clinical concentrations of gentamicin and alternatives, ceftazidime and meropenem, on ureteric branching. METHODS: Mice metanephroi were dissected at embryonic day 13 and cultured in media with or without various concentrations of gentamicin, ceftazidime, or meropenem. Zero and 24 h kidney size were assessed by surface area measurements, and the ureteric tree was visualized by whole mount staining and confocal microscopy. Branching was evaluated by counting and gene expression levels of Wt1, Sox9, Bmp7, Fgf8, and Gdnf were investigated. RESULTS: A concentration of 2,000 µmol/l ceftazidime impaired ureteric development. In addition, a 4.5-fold and a 2.5-fold downregulation was noted in Fgf8 and Gdnf, respectively. No adverse effects were noted after gentamicin or meropenem treatment. No relationship was noted between surface area expansion and ureteric bud formation, but surface area at explantation related to bud count after 24 h of culture. CONCLUSION: Ceftazidime, but not gentamicin or meropenem reduced ureteric branching in mice and suggest a role for Fgf8 and Gdnf in its mechanism. Metanephros surface area measurements can be used to reduce intra- and inter-litter variation.

Immunomodulatory effects of ciprofloxacin in TNBS-induced colitis in mice.

BACKGROUND: Crohn's exacerbation and pouchitis are commonly treated with ciprofloxacin and metronidazole. Few studies have shown an advantage of this regimen compared with other antibiotics. Most attributed the effect to its better antibacterial coverage. Others have shown an apparent anti-inflammatory effect of quinolones in several in vitro and in vivo models of inflammation other than inflammatory bowel diseases (IBD). Our objective was to test the hypothesis that ciprofloxacin may act as an anti-inflammatory agent rather than just an antibacterial drug using a model of chemical colitis. METHODS: TNBS colitis was induced in BALB/c mice. The anti-inflammatory effect of ciprofloxacin compared with ceftazidime and dexamethasone was assessed. RESULTS: Mice treated with ciprofloxacin (7.5 mg/kg or 15 mg/kg) had significant reductions in clinical signs, body weight loss, splenic and colonic weight increase compared with saline-treated and ceftazidime-treated mice. Histologic analysis showed mild inflammation in ciprofloxacin-treated mice with a mean score of 3.8 +/- 0.5 points compared with moderate colitis scored 7.8 +/- 1.3 and 9.5 +/- 0.5 points in saline and ceftazidime-treated mice, respectively. Analysis of cytokine levels in colon homogenates showed a significant decrease of IL-1beta, IL-8, and TNFalpha levels in ciprofloxacin-treated animals. Immunohistochemistry for NFkappaB showed strong positivity in saline and ceftazidime-treated mice in contrast to weak focal stain in ciprofloxacin- and dexamethasone-treated mice. CONCLUSIONS: These findings imply that ciprofloxacin has an anti-inflammatory effect, rather than just an antibacterial one, making its use favorable in IBD patients.

Retinal toxicity of intraocular vancomycin and ceftazidime in vitrectomized rabbit eyes.

The purpose of this study was to evaluate the retinal toxicity of vancomycin and ceftazidime combined into an infusion solution that was intraoculary given after or during vitrectomy. Forty albino rabbits were divided into 4 groups of 10 each. Vitrectomized right eyes of groups 1, 2, and 3 were given recommended doses of vancomycin and ceftazidime alone or combined, while right eyes in the fourth group were vitrectomized using an infusion solution to which was added ceftazidime and vancomycin combination. Toxicity was tested with electroretinography (ERG) and light microscopy. ERG and light microscopy did not show any toxicity signs associated with vancomycin or ceftazidime alone or with combined therapy. Vancomycin and/or ceftazidime can reliably and effectively be used combined in an infusion solution at recommended doses after and during vitrectomy. This treatment modality does not have any toxic effects to retinal structures and is an alternative method to separate injections of the two antimicrobial agents.

Drugs toxic to the bone marrow that target the stromal cells.

Drugs that cause toxicity to the bone marrow are a heterogeneous group of compounds that act by various mechanisms. The etiology of this pathology is poorly understood but the highly proliferative nature of the hematopoietic cells is assumed to make the bone marrow more sensitive to toxicity. Recent evidence suggests that drugs can also affect specific aspects of stromal cells and the extracellular matrix that they establish. The data support the view that characteristics other than a high proliferation rate could confer susceptibility of the bone marrow to the toxic effects of drugs. This article discusses those drugs that have been shown to have direct effects on the bone marrow stromal cells.

Evaluation of toxicity of intravitreal ceftazidime, vancomycin, and ganciclovir in a silicone oil-filled eye.

PURPOSE: To evaluate the toxicity of intravitreal drugs in an eye filled with silicone oil for prolonged internal retinal tamponade. METHODS: Vitrectomy was performed in 21 rabbit eyes, and the vitreous was replaced with silicone oil. Different concentrations of various drugs (ceftazidime, vancomycin, and ganciclovir) were injected intravitreally. RESULTS: Silicone oil increased the toxicity of these drugs, which were injected in previously determined nontoxic doses, possibly because of a reduction of the preretinal space. Injecting one quarter of the known nontoxic dose failed to show any toxicity. CONCLUSIONS: Nontoxic concentrations of intravitreal drugs can cause toxicity in a silicone-filled eye.

Safety of repeated intravitreous injections of antibiotics and dexamethasone.

PURPOSE: To determine the retinotoxicity of repeated intravitreous injections of vancomycin, ceftazidime, and dexamethasone in rabbit eyes. METHODS: Twenty pigmented New Zealand rabbits were divided into two groups. In Group 1, the right eyes received repeated intravitreous injections with vancomycin 0.3 mg, ceftazidime 0.7 mg, and dexamethasone sodium phosphate 0.13 mg at three consecutive 48-hour intervals. Group 2 right eyes received three times higher dose of the same intravitreous drugs as used in Group 1, repeated at the same frequency. All left eyes served as control eyes. Retinotoxicity was monitored by slit-lamp biomicroscopy, indirect ophthalmoscopy, electroretinography, and light and electron microscopy. RESULTS: No evidence of retinotoxicity was found in Group 1 eyes. Photopic A-waves were significantly elevated, and 30- and 50-Hz flicker fusion amplitudes were significantly depressed in Group 2 eyes. No changes were found by clinical or histopathologic examination in the retinas of either group. CONCLUSIONS: Three repeated intravitreous injections at 48-hour intervals of a combination of vancomycin, ceftazidime, and dexamethasone in rabbit eyes at dosages that approximate drug concentrations recommended for human endophthalmitis were nontoxic. Similar injections at three times higher doses resulted in mild electroretinogram changes.

Protective effects of a human 18-kilodalton cationic antimicrobial protein (CAP18)-derived peptide against murine endotoxemia.

CAP18 (an 18-kDa cationic antimicrobial protein) is a granulocyte-derived protein that can bind lipopolysaccharide (LPS) and inhibit various activities of LPS in vitro. The present study examined the protective effect of a synthetic 27-amino-acid peptide (CAP18(109-135)) from the LPS-binding domain of CAP18 against antibiotic-induced endotoxin shock, using highly LPS-sensitive D-(+)-galactosamine (D-GalN)-sensitized C3H/HeN mice. The antibiotic-induced endotoxin (CAZ-endotoxin) was prepared from the culture filtrate of Pseudomonas aeruginosa PAO1 exposed to ceftazidime (CAZ). Injection of CAP18(109-135) protected the mice injected with LPS or CAZ-endotoxin from death and lowered their tumor necrosis factor (TNF) levels in serum in a dose-dependent manner. Treatment with CAZ caused death of the D-GalN-sensitized P. aeruginosa PAO-infected mice within 48 h, while injection with CAP18(109-135) rescued the mice from death. In the mice rescued from death by injection with CAP18(109-135), endotoxin levels in plasma and TNF production by liver tissues were decreased but the numbers of viable infecting bacteria in their blood were not decreased significantly and remained at the levels in CAZ-treated mice. These results indicate that CAP18(109-135) is capable of preventing antibiotic-induced endotoxic shock in mice with septicemia and that the effect is due to its LPS-neutralizing activity rather than to its antibacterial activity.

Endothelial toxicity of ceftazidime in anterior chamber irrigation solution.

Due to the high toxicity of aminoglycoside antibiotics, many authors prefer to use third generation cephalosporines in the prophylaxis and treatment of intraocular infections. The aim of the present study was to determine safe ceftazidime levels in anterior chamber irrigation solution. Twenty-two eyes of 12 white New Zealand rabbits were divided into six groups of two animals each. Double paracentesis was performed in both eyes, irrigating the right eye with 250 ml of BSS-Plus (BSS+) solution, and the left eye with 250 ml of BSS+ solution with increasing concentrations of ceftazidime (2, 3, 4, 6 and 8 mg ml-1). Each rabbit was killed at the end of surgery, except the last group, which received BSS+ and BSS+ with 8 mg ml-1 of ceftazidime, respectively, in one eye, and were then killed 24 hr later. Endothelial lesions were assessed by silver nitrate staining. We considered lesions endothelial silver affinity ranging from minimal (1-2+) to intense (3-4+). 1-2+ silver affinity was found in 4 +/- 1.35% of endothelial cells in the controls; this percentage in turn increased with antibiotic concentration (6.1 +/- 1.13%, 6.7 +/- 0.4%, 7.2 +/- 1.36%, 7.3 +/- 1.93% and 7.5 +/- 1.83%, respectively). The percentage of 3-4+ silver affinity was 0.18 +/- 0.17% in the controls, and likewise increased with antibiotic concentration (0.22 +/- 0.11%, 0.37 +/- 0.09%, 2.8 +/- 0.63% and 3.1 +/- 0.46%, respectively). The increase in affinity was greatest up to the 4 mg ml-1 concentration. In the last group there were zones of endothelial alterations in morphology and size, with signs of attempted repair in the eye treated with antibiotic, but none in the case treated only with BSS+. Ceftazidime concentrations above 3 mg ml-1 in intraocular infusions induce endothelial cell toxicity.

Non-toxic concentrations of cephem antibiotics for intravitreal application--evaluation by in vitro electroretinogram.

Non-toxic concentrations of ceftazidime (CAZ), cefuzonam sodium (CZON) and cefmetazole sodium (CMZ) for intravitreal use were assessed by the electroretinogram in in vitro perfused eyecups of albino rabbits. None of the a-wave, the b-wave and the oscillatory potentials deteriorated with 300 microM CAZ, 300 microM CZON or 500 microM CMZ. The oscillatory potentials were delayed and/or diminished at the concentration which did not change the a- and b-waves (500 microM and 1.0 mM for CAZ and CZON, 1.0 mM for CMZ). Thus, the oscillatory potentials were more vulnerable to these chemicals than the a- and b-waves. Not only the classical a- and b-waves, but also the oscillatory potentials should be examined in retinal toxicology studies by the electroretinogram.

[The transplacental transit and action of ceftazidime on the fetus in an experiment on animals at different times of the pregnancy]. / Transplatsentarnyi perekhod i deistvie tseftazidima na plod v éksperimente u zhivotnykh v raznye sroki beremennosti.

The experiments were conducted on pregnant albino rats to study the transplacental transit of ceftazidime (Fortum) to the fetus on days 14 and 21 of pregnancy after a single intramuscular injection of 100 mg/kg. The antibiotic transition was 5.23, and 51.94% on days 14 and 21, respectively. The total toxic and embryotoxic effects of ceftazidime were studied in pregnant albino rats given intramuscular injections of 100 and 500 mg/kg/day on days 9-20 of pregnancy. Ceftazidime was found to have neither negative effects on the maternal body and nor embryotoxic and teratogenic properties.

Two-dimensional polyacrylamide gel electrophoresis isolation and microsequencing of Pseudomonas aeruginosa proteins.

Outer membrane (OM) proteins of beta-lactam-susceptible and -resistant strains of Pseudomonas aeruginosa were analyzed by 2-D polyacrylamide gel electrophoresis. Carrier ampholytes, pH 4-8, and immobilized pH gradient (IPG), pH 3.5-10.0, procedures were used. An acidic-protein spot (pI = 5.2) detected in susceptible but not in an imipenem-resistant strain was sequenced and twenty-five N-terminal amino acids had total homology with the OM protein D, the imipenem-specific porin of P. aeruginosa. A basic-protein spot (pI = 9.0) detected in ceftazidime-resistant, but not in a susceptible strain was sequenced and fourteen N-terminal amino acids had homology with a beta-lactamase encoded by the ampC gene of P. aeruginosa. The IPG procedure allows identification of more than one hundred proteins of the OM fraction from a single gel. Detection of beta-lactamase in OM fractions might reflect a periplasmic contamination, but its anchorage within the OM cannot be ruled out.

Toxicity of intravitreous ceftazidime in primate retina.

Squirrel monkeys were anesthetized and given intravitreous injections of 0.1 mL of balanced salt solution containing 0 mg (two eyes), 1 mg (three eyes), 2.25 mg (three eyes), or 10 mg (three eyes) of ceftazidime, a third-generation cephalosporin that provides excellent coverage for gram-negative infections. Ophthalmoscopic examinations were performed 48 hours after the injections and results were completely normal in all eyes except for those that were injected with 10 mg of ceftazidime, all three of which showed the appearance of cystic change in the macula. The monkeys were killed and the eyes were removed and examined by light and electron microscopy. All eyes were normal by light microscopy except for those injected with 10 mg of ceftazidime, which showed disruption of photoreceptors (primarily outer segments) in the foveas with cystic changes in all three and macular holes in two of three. Electron microscopy showed mild swelling of mitochondria and perinuclear halos around photoreceptor nuclei in both control eyes and in eyes injected with 1 and 2.25 mg. An eye injected with 10 mg showed severe damage to central photoreceptor outer segments consisting of disruption of plasma membranes and accumulation of intracytoplasmic granular material. Inner segments showed mild changes and there was loss of apical microvilli of the retinal pigmented epithelium. The inner retina was normal. These data suggest that high doses of intravitreous ceftazidime show toxicity primarily to photoreceptor cells, but a dose of 2.25 mg is safe as studied in this model and can be used instead of intravitreous aminoglycosides that have a narrow therapeutic window.

Nontoxic concentration of ceftazidime and flomoxef sodium for intravitreal use--evaluated by in-vitro ERG.

The effects of ceftazidime (CAZ) and flomoxef sodium (FMOX) on the in-vitro electroretinogram (ERG) of albino rabbits were studied. The a-wave, the b-wave and the oscillatory potential (OP) were unchanged by 0.3mM (0.19mg/ml) CAZ-containing solution. The OP was suppressed by 0.5mM (0.32mg/ml) CAZ. The a-wave, the b-wave and the OP were unchanged by 0.5mM (0.26mg/ml) FMOX. The OP was suppressed and its peak latency was delayed by 2mM (0.52mg/ml) FMOX. The concentration of 0.3mM (0.19mg/ml) CAZ was higher than its minimum inhibitory concentration (MIC) against Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, Serratia marcescens and Propionibacterium acnes. The concentration of 0.5mM (0.26mg/ml) FMOX was higher than its MIC against Staphylococcus aureus, Staphylococcus epidermidis, Serratia marcescens and Propionibacterium acnes.

Safety evaluation of meropenem in animals: studies on the kidney.

The effect of meropenem on animal kidneys has been assessed in rats (5 of each sex/group), rabbits (3 of each sex/group) and monkeys (3 of each sex/group) in comparative iv studies with ceftazidime, cefotaxime, cephaloridine and imipenem (without cilastatin). Diarrhoea occurred in rabbits and monkeys dosed with imipenem or meropenem. Emesis occurred only after the administration of imipenem to monkeys. After 14 days administration to rats evidence of nephrotoxicity was seen only in males dosed with cephaloridine (850 mg/kg); no changes were seen with ceftazidime, cefotaxime or meropenem (all at 1000 mg/kg). Four days after a single dose to rabbits renal tubular necrosis was seen in all animals receiving imipenem (150 mg/kg) and cephaloridine (250 mg/kg). Minimal histopathological changes to the kidneys were seen with cefotaxime, ceftazidime and meropenem (all at 400 mg/kg). After seven days' administration to cynomolgus monkeys imipenem (180 mg/kg) caused moderate to severe tubular necrosis. No tubular damage was seen with meropenem at 180 mg/kg or with cefotaxime or ceftazidime (both at 500 mg/kg). At 500 mg/kg meropenem caused mild tubular regeneration and/or fat accumulation in 3/6 animals, with mild tubular necrosis in one of these. The data from these three species indicate that meropenem has a low nephrotoxic potential in these animal models.

The ototoxicity of ceftazidime in the chinchilla middle ear.

Ceftazidime (Tazicef) is a broad-spectrum cephalosporin antibiotic that may be useful as a topical agent in the treatment of otorrhea. To test the potential ototoxicity of the drug, 0.5 mL of a 10% solution of ceftazidime was introduced into the bullae of 22 chinchillas. The organ of Corti was normal in 20 temporal bones examined at 1 week after administration of the ceftazidime solution. Only 2 of 24 temporal bones examined after 4 weeks showed minor outer hair cell loss of the basal turn of the organ of Corti. Focal hemorrhage and occasional serous effusions were found in the middle ears of all animals after 1 week; these findings had mostly cleared after 4 weeks. Our results indicate that ceftazidime causes reversible middle ear inflammation, and may have some minor ototoxic potential under these experimental conditions.