Cefodizime Research Articles

Probing the interaction of cefodizime with human serum albumin using multi-spectroscopic and molecular docking techniques

To know the interaction of cefodizime (CEF) with human serum albumin (HSA), techniques of different spectroscopies and molecular modeling were used. The inner filter effects were eliminated to get accurate binding parameters. Steady state fluorescence suggested a static type for CEF–HSA interaction, and the complex formation had a high affinity of 105Lmol−1. On the basis of the thermodynamic results and site marker competitive experiments, it was considered that CEF was bound to site I (subdomain IIA) of HSA mainly by hydrogen bonds and van der Waals force. The calculated binding distance (r) indicated that the non-radioactive energy transfer came into being in the interaction between CEF and HSA. Furthermore, molecular modeling was applied to further define that CEF interacted with the Trp214, Lys199, Phe211, Leu238 residues of HSA. In addition, three-dimensional fluorescence and circular dichroism (CD) results showed that the binding of CEF can cause conformational and some microenvironmental changes of HSA. This paper provides reasonable models helping us further understand the transportation and distribution of CEF when it spreads into human blood serum which is of great importance in pharmacology and pharmacodynamics.

Fluctuations in elastase of cervical mucus and clinical efficacy of cefodizime in obstetric and gynecologic infections.

Clinical efficacy of cefodizime (CDZM) in obstetric and gynecologic infections and in their prevention, and fluctuations in cervical mucus elastase in gynecologic infections and during pregnancy were studied, and the following results were obtained: 1. Cervical mucus elastase showed high values of > or = 5,001 micrograms/L in 68.2% of non-pregnant patients and in 25.9% of pregnant patients (gestational age of 24-42 weeks). Patients with concomitant chorioamnionitis showed a significantly higher rate of elastase elevation than those without this complication (63.2% vs. 25.9%, P < 0.005). 2. Cervical mucus elastase in uterine and pelvic infections showed high values before administration of CDZM but tended to decline with the progress of cure (15/19 cases, 78.9%). 3. The efficacy rate of 2-4 g/day of CDZM drip infusion against infections was 53/56 (94.6%) while the bacterial eradication rate was 36/38 (94.7%). The efficacy rate of 2 g/day of CDZM drip infusion for the prevention of postoperative infections was 429/431 (99.8%). Diarrhea occurred in 3/489 (0.6%) as subjective and objective side effects. Slight rises in GOT and GPT were noted in 13/486 (2.7%) as abnormal laboratory values. These results suggested the usefulness of CDZM in the obstetric and gynecologic fields.

In vivo antibacterial activity of cefodizime, a new cephalosporin antibiotic.

The in vivo activity of cefodizime (HR 221) was compared with that of cefotaxime (CTX), cefmenoxime, latamoxef, cefazolin and cefmetazole (CMZ). The protective effects of HR 221 on experimental infections in mice caused by Staphylococcus aureus Smith, Escherichia coli C-11, Proteus vulgaris GN-76 and Serratia marcescens No. 2 were directly related to its in vitro activity against these strains. In contrast, the compound showed the smallest ED50 values, among the 5 antibiotics tested (not including CMZ), for Klebsiella pneumoniae 3K-25 and Pseudomonas aeruginosa PI 67 against which it had relatively low in vitro activity, and its ED50 for Citrobacter freundii GN-346 was as small as 1.821 mg/mouse in spite of its MIC of greater than 100 micrograms/ml. HR 221 exerted potent bactericidal activity against Streptococcus pneumoniae Sp-1 inoculated into the mouse lung; the duration of action was prolonged. When tested against the E. coli Ec-89 infection induced in the rat uterus, the activity of HR 221 given to rats once daily was equal to that of CTX or CMZ given at the same dose twice daily.

In vitro activities of antimicrobial combinations against clinical isolates of Neisseria gonorrhoeae

The Centers for Disease Control and Prevention (CDC) now recommend combination therapy with ceftriaxone 250 mg plus azithromycin (AZM) 1 g as a first-line regimen for gonorrhea because the increase of Neisseria gonorrhoeae resistant to multiple antimicrobial agents. However, reports on the in vitro activity of antimicrobial combinations against clinical isolates of N. gonorrhoeae are very rare. In the present study, a checkerboard method was utilized to examine the in vitro activity of ceftriaxone (CTRX), cefodizime (CDZM), spectinomycin (SPCM), or gentamicin (GM) in combination with AZM against 25 clinical isolates of N. gonorrhoeae. The SPCM + AZM combination demonstrated the lowest mean fractional inhibitory concentration index (FICI) of 0.69, followed by the CDZM + AZM combination (mean FICI, 0.75), the CTRX + AZM combination (mean FICI, 0.81), and the GM + AZM combination (mean FICI, 0.83). Additivity/indifference effect was detected for the SPCM + AZM combination, the CDZM + AZM combination, the CTRX + AZM combination, and the GM + AZM combination, against 96%, 72%, 92%, and 100% of the isolates, respectively. There was no antagonism for any of the antimicrobial combinations against the 25 N. gonorrhoeae isolates. These results suggest that the antimicrobial combinations may be worthy of clinical evaluation as an alternative regimen for gonococcal infections caused by antimicrobial-resistant strains.

Therapeutic effect of granulocyte colony-stimulating factor and cephem antibiotics against experimental infections in neutropenic mice induced by cyclophosphamide.

Effects of recombinant human granulocyte colony-stimulating factor (rhG-CSF) against severe infections in cyclophosphamide (CY)-induced neutropenic mice were investigated by its single use or by its combination with cephem antibiotics. Treatment with rhG-CSF increased the number of peripheral blood leucocytes and strikingly shortened the duration of the neutropenic state. Most of the regained population in the peripheral blood leucocytes were neutrophils. Functions of neutrophils, such as phagocytic activity, superoxide release, and expression of Mac-1 molecules, were remarkably enhanced by administration of rhG-CSF. When rhG-CSF was administered to CY-induced neutropenic mice before infection, protective effects against various kinds of bacteria were remarkable. On the other hand, such remarkable effects were not observed when rhG-CSF was administered after infections. However, even in the case of post-infectious treatment, a combination therapy of rhG-CSF with cephem antibiotics, particularly with Cefodizime (CDZM), showed a significant improvement in the survival rate and a decrease in the number of viable bacteria in the liver. These results suggest that a combination therapy of rhG-CSF with cephem antibiotics, especially with CDZM, is an efficient regime against severe infections in patients with neutropenia induced by a heavy anti-tumour chemotherapy.

Multiple doses of cefodizime are necessary for the treatment of Neisseria gonorrhoeae pharyngeal infection

A single dose of cefodizime (CDZM), ceftriaxone (CTRX), or spectinomycin (SPCM) is recommended for the treatment of gonococcal urethritis or uterine cervicitis in the era of multidrug-resistant Neisseria gonorrhoeae; namely, cefozopran-resistant N. gonorrhoeae (CZRNG). N. gonorrhoeae pharyngeal infection is not so rare in Japan; however, the proper treatment regimen for this infection is not clear. We previously found that a single dose of CDZM completely eradicated multidrug-resistant N. gonorrhoeae in patients with urethritis and uterine cervicitis, so we tried a single 1.0-g dose of CDZM for the treatment of N. gonorrhoeae pharyngeal infection, including infections with CZRNG. The eradication rate of N. gonorrhoeae from the pharynx was 63.0% with a single 1.0-g dose of CDZM, while the rate for CZRNG with the same dose of CDZM was 38.5%. N. gonorrhoeae was completely eradicated from the pharynx when patients received one or two additional doses of CDZM. Therefore, we concluded that two to three doses of CDZM were necessary for the treatment of N. gonorrhoeae pharyngeal infection including infection with CZRNG.

Single dose of cefodizime completely eradicated multidrug-resistant strain of Neisseria gonorrhoeae in urethritis and uterine cervicitis

Cefodizime (CDZM) has strong antimicrobial activity to Neisseria gonorrhoeae in vitro. However, multidrug-resistant N. gonorrhoea emerged and has been increasing in Japan. To know the effectiveness of CDZM on gonococcal urethritis and uterine cervicitis even in the era of multidrug-resistant N. gonorrhoeae, a clinical trial of single-dose therapy of CDZM for gonococcal urethritis and uterine cervicitis was conducted. N. gonorrhoeae was eradicated from 100% of patients with gonococcal urethritis and uterine cervicitis by a single dose of CDZM. In conclusion, CDZM is one of most suitable drugs for the treatment of gonococcal genital infection in the era of multidrug-resistant N. gonorrhoeae.

Cefodizime enhances phagocytosis and intracellular killing of Staphylococcus aureus but does not influence polymorphonuclear leukocytes response to fMLP stimulation

The influence of Cefodizime (CDZ) on in vitro activity of polymorphonuclear leukocytes (PMNL) from healthy subjects was assessed. Preincubation with CDZ enhanced phagocytosis and intracellular killing of Staphylococcus aureus by PMNL. Contrary to numerous clinical reports, no significant effect of CDZ preincubation on PMNL response to n-formyl-methionyl-leucyl-phenylalanine was found with respect to intracellular calcium changes, degranulation, hydrogen peroxide production, and chemiluminescence. These results suggest that augmented microbicidal activity of PMNL is not related to the enhanced production of reactive oxygen species in healthy subjects.

Cefodizime enhances phagocytosis and intracellular killing of Staphylococcus aureus but does not influence polymorphonuclear leukocytes response to FMLP stimulation

The influence of Cefodizime (CDZ) on in vitro activity of polymorphonuclear leukocytes (PMNL) from healthy subjects was assessed. Preincubation with CDZ enhanced phagocytosis and intracellular killing of Staphylococcus aureus by PMNL. Contrary to numerous clinical reports, no significant effect of CDZ preincubation on PMNL response to n-formyl-methionyl-leucyl-phenylalanine was found with respect to intracellular calcium changes, degranulation, hydrogen peroxide production, and chemiluminescence. These results suggest that augmented microbicidal activity of PMNL is not related to the enhanced production of reactive oxygen species in healthy subjects.

Influence of cefodizime on pulmonary inflammatory response to heat-killed Klebsiella pneumoniae in mice.

Encapsulated Klebsiella pneumoniae strains frequently induce fatal nosocomial pneumonia. Cefodizime (CEF) as an antibiotic is suspected to enhance host resistance against various microbial invasions through interactions with bacteria and host cells. To investigate the influence of CEF on the pulmonary response to Klebsiella that does not merely result from direct bacterial clearance by the drug, we inoculated mice with heat-killed fluorescein isothiocyanate-labeled K. pneumoniae. CEF upregulated (P < 0.01) the early Klebsiella-induced secretion of tumor necrosis factor alpha, as well as the number (P < 0.01) and phagocytic efficacy (P < 0.001) of alveolar macrophages. By contrast, the late polymorphonuclear neutrophil recruitment (P < 0.05) and levels of interleukin-1 alpha (IL-1alpha) (P < 0.05) and IL-6 (P < 0.05) were reduced. The stimulation of an early immune response by CEF followed by late reduction in inflammation may be beneficial against bacterial pneumonia.

Reduction by cefodizime of the pulmonary inflammatory response induced by heat-killed Streptococcus pneumoniae in mice.

It has recently become apparent that overwhelming inflammatory reactions contribute to the high mortality rate associated with pneumococcal infection in immunocompetent hosts. Cefodizime (CEF) is an antibiotic that seems to be endowed with immunomodulating properties. To investigate the influence of CEF on the pulmonary inflammatory response induced by Streptococcus pneumoniae, we infected mice with repeated intranasal inoculations of 10(7) CFU of heat-killed fluorescein isothiocyanate-labeled bacteria, which are insensitive to the killing properties of the drug. CEF downregulated but did not abolish the strong polymorphonuclear leukocyte (PMN) recruitment induced by S. pneumoniae. PMN recruitment was not primarily mediated by leukotriene B4 in this model. The drug did not interfere with intrinsic mechanisms of phagocytosis by PMNs and alveolar macrophages. CEF totally abrogated the pneumococcus-induced tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) secretion in bronchoalveolar lavage fluid. The drug also prevented IL-6 release in lung homogenates and partly inhibited TNF-alpha, but it did not interfere with IL-1alpha secretion in the lungs of infected mice. The fractional and selective downregulation of inflammatory cells and cytokines by CEF suggests cell-specific and intracellular specific mechanisms of interaction of the drug. The immunomodulatory properties of CEF may help restrain excessive inflammatory reactions, thus contributing to the reported good clinical efficacy of the drug against lower respiratory tract infections.

Reduced anti-Pseudomonas aeruginosa activity of a cephalosporin, cefodizime, in rats whose neutrophils were selectively depleted by a monoclonal antibody.

In order to clarify the mechanisms of the in vivo antibacterial activity of a cephalosporin, cefodizime (CDZM), the effect of this antibiotic on Pseudomonas aeruginosa E7 infection was examined in rats whose neutrophils had been selectively depleted by monoclonal antibody RP-3. CDZM was less effective in RP-3-treated rats than in untreated rats. However, treatment of rats with recombinant human granulocyte-colony stimulating factor (rhG-CSF) augmented the in vivo activity of this antibiotic. Furthermore, the in vivo antibacterial activity of two other cephalosporins, cefpimizole (CPIZ) and cefoperazone (CPZ), was bilaterally affected by a rise or fall in the neutrophil number, although to a lesser degree than was the case with CDZM. Taken together, neutrophils play an important role in the in vivo antibacterial activity of certain cephalosporins.

Cefodizime modulates in vitro tumor necrosis factor-alpha, interleukin-6 and interleukin-8 release from human peripheral monocytes.

Among third-generation cephalosporins, cefodizime (CFDZ) has shown to modulate many functions of the host defense system against infections. The aim of the present study was to assess the in vitro CFDZ-dependent modulation of interleukin (IL)-6, tumor necrosis factor-alpha (TNF-alpha) and IL-8 release from lipopolysaccharide (LPS)-stimulated human peripheral mononuclear cells (MNCs). Two other third-generation cephalosporins: ceftriaxone (CFX) and ceftazidime (CFT), were also tested under the same experimental conditions. At concentrations ranging from 200 to 50 micrograms/ml, CFDZ significantly decreased TNF-alpha and IL-6 release from maximally (LPS 1 microgram/ml) stimulated MNCs (42% inhibition of TNF-alpha release with 100 micrograms/ml of CFDZ). On the other hand, CFDZ revealed a marked stimulatory effect on IL-8 release (200 micrograms/ml of CFDZ induced 51.5% enhancement of IL-8 release). On the contrary, both CFX and CFT failed to exert any significant effect on TNF-alpha, IL-6 or IL-8 release.

Reevaluation of current antimicrobials: cefodizime. Discussion

Reevaluation of current antimicrobials: cefodizime. Discussion

Comparative Study of the Effects of Cefodizime and HBW 538 in Potentiating the Production of Reactive Oxygen Species by Human Polymorphonuclear Leukocytes

The immunomodulatory activity of cefodizime (CDZM), an aminothiazolylcephalosporin, was compared to that of HBW 538, a derivative of the CDZM side chain at position 3 (the mercaptothiazolyl group) in respect to the production of reactive oxygen species (ROS) by human whole blood and polymorphonuclear leukocytes (PMN) in vitro. Ten-fold diluted whole blood and PMN from healthy individuals were incubated with CDZM or HBW 538 alone at the concentrations of 1, 10, or 100 micrograms/ml, or CDZM or HBW 538 at 100 micrograms/ml in combination with tumor necrosis factor-alpha (TNF-alpha) at 100 U/ml or lipopolysaccharide (LPS) at 1 microgram/ml. The production of ROS was measured by a chemiluminescence (CL) assay in which luminol was added to a mixture and after which the PMN or whole blood were stimulated with nonopsonized zymosan or phorbol myristate acetate. The following results were obtained: (1) The CL responses of whole blood and PMN were slightly but not significantly enhanced by CDZM at 100 micrograms/ml, whereas both CL responses were significantly enhanced by exposure to HBW 538 at 10 and 100 micrograms/ml. (2) The enhanced PMN CL response which followed priming with TNF-alpha or LPS was not augmented by CDZM but was significantly augmented by HBW 538. These results indicate that the ability of the HBW 538 molecule to enhance the production of ROS by stimulated PMN and to act agonistically with TNF-alpha or LPS is abrogated when HBW 538 is part of the CDZM molecule.(ABSTRACT TRUNCATED AT 250 WORDS)

Ｃｅｆｏｄｉｚｉｍｅ（ＣＤＺＭ，ケニセフ）のヒト口腔組織移行に関する薬動力学的検討

To study the feasibility of employing cefodizime (CDZM) in the field of oral surgery, a pharmacokinetic analysis was performed for CDZM concentrations in the oral tissues after intravenous injection of 1g CDZM in 26 patients.The following results were obtained:1) The half-life of CDZM in serum was calculated to be 2.64 hours.2) The peak concentrations of CDZM were 13.03 μg/g in the gum, 4.84 μg/g in the bone and 17.06 μg/g in the cyst wall. The AUC of CDZM in oral tissue to that in serum was 12.53% in the gum, 3.26% in the bone, and 8.23% in the cyst wall.

A study of the efficacy and safety of cefodizime (CDZM) and gentamicin (GM) combination therapy in severe infections associated with hematologic disorders

A study of the efficacy and safety of cefodizime (CDZM) and gentamicin (GM) combination therapy in severe infections associated with hematologic disorders

Erratum to: Cefodizime

Erratum to: Cefodizime

No safety concerns with cefodizime

No safety concerns with cefodizime

Safety profile of cefodizime

The results of animal toxicology studies with cefodizime (CDZ) showed no reason for concern with respect to drug safety. Renal tolerance of CDZ proved to be better than that observed with other cephalosporins; furthermore, CDZ had no adverse effects on spermatogenesis, fertility or embryonic development. A total of 6,299 patients were treated with CDZ in clinical trials worldwide, while 1,225 patients received cefuroxime, cefotaxime, cefmenoxime or cefizoxime in comparative studies. The incidence of mortality in the repeated dose trials was 1.6% (CDZ) and 1.75% (comparators); the incidence of adverse drug reactions (ADRs) was 3.06% and 3.64%, respectively. ADRs were mostly of gastrointestinal or allergic nature. In no case was a causative relationship established between CDZ and the death of a patient. Any influence of CDZ on platelet count and function, plasma coagulation and vitamin K metabolism has been excluded. Cefodizime has a favorable risk/benefit ratio.