Consensus guidance of nebulizer therapy for acute rhinosinusitis.

The guidance deals with the recommended applications, procedures, and safety management of nebulizer therapy for acute rhinosinusitis. In Japan, nebulizer therapy for sinusitis has been covered by public health insurance since 1958 and has been commonly carried out nationwide. The Japan Society for Infection and Aerosol in Otorhinolaryngology and the Oto-Rhino-Laryngological Society of Japan set up a working group to draw up a consensus guidance on nebulizer therapy for acute rhinosinusitis. The device for nebulizer therapy are classified into jet, ultrasound, and mesh types. In Japan, cefmenoxime hydrochloride (CMX) was approved for use in nebulizer therapy since 1996. The widening of the obstructed lesions such as large polyps prior to nebulizer therapy were recommended. The numbers of times of nebulizer therapy is recommended for three times in a week for at least for 2 weeks (cure rate: 68%, eradication ratio: 48%). Concerns should be pay for the changes of activity of medicine due to the mixing and bacterial contamination. Pseudomonas cepacia growing in a short even in both saline and distilled water leads to contamination at high concentrations by 2 days. Nebulizer therapy is an effective treatment based on a drug delivery system (DDS) to the nasal and paranasal cavities. The therapy effectively increases the local drug concentration by promptly and uniformly delivering drugs to a targeted local site. The therapy is safe with less systemic absorption and with few adverse reactions.

Pharmacokinetics and bioequivalence studies of cefteram pivoxil in healthy Chinese volunteers.

A simple, sensitive and specific method has been developed for the determination of cefteram in human plasma. Sample preparation was accomplished through protein precipitation with 20% trichloroacetic acid (v/v) and chromatographic separation was performed on a C18 column at 25 degrees C. The mobile phase consisted of methanol-aqueous 20 mM ammonium acetate (18:82, v/v) at flow rate of 1.0 mL/min. Wavelength was set at 235 nm. The lower limit of quantification was 0.04 microg/mL and the assay exhibited a linear range of 0.04-3.2 microg/mL (r=0.9996). The relative recoveries of cefteram from human plasma at three different concentrations were more than 90%. The method was successfully applied to investigate the bioequivalence between two kinds of cefteram pivoxil preparations (test vs reference) in 24 healthy Chinese volunteers. After a single 100 mg dose for the test and reference product, the resulting means of major pharmacokinetic parameters such as AUC(0-t), AUC(0-infinity), Cmax and Tmax of cefteram pivoxil were 4.75 +/- 1.35 vs 4.76 +/- 1.29 microg h/mL, 4.89 +/- 1.36 vs 4.91 +/- 1.29 microg h/mL, 1.65 +/- 0.45 vs 1.73 +/- 0.45 microg/mL and 1.48 +/- 0.59 vs 1.73 +/- 0.45 h, respectively, indicating that these two kinds of preparations were bioequivalent.

[Evaluation of antimicrobial prophylaxis after normal delivery].

In Japan, as a measure to prevent puerperal infection, oral antimicrobial prophylaxis has been conducted after delivery in many maternity clinics. However, there are only a few reports on the evidence supporting the validity of antimicrobial prophylaxis following normal delivery. There is concern that unnecessary antimicrobial administration may be conducted in such clinics. In the present study, the puerperal females after normal delivery were placed on different treatments. A group of females received no oral antimicrobial administration. The remaining females were given cefteram pivoxil (CFTM-PI) in the two different doses. In this manner, we evaluated usefulness of antimicrobial prophylaxis. We compared three treatment groups with respect to the incidence of infection for the period until the first week after discharge, and obtained the following results: non-antimicrobial prophylaxis group (group A), 5.83%; antimicrobial prophylaxis group (group B), 1.77%; antimicrobial prophylaxis group (group C), 0%. In group B, the puerperal females were orally given CFTM-PI in a total daily dose of 300 mg, three times daily for three days. In group C, the puerperal females were orally given CFTM-PI in a total daily dose of 300 mg, three times daily for five days. The incidence of infection was the lowest in group C which was followed by group B and group A in this order and the significant intergroup difference was recognized (p=0.004). We also compared the total counts of bacteria, aerobes and anaerobes in lochia on the fifth day during the puerperal period with those on the first day in each treatment group. The decrease in bacterial count was the largest in group C, which was followed by group B and group A in this order. Compared with the total bacterial counts obtained on the first day, those obtained on the fifth day decreased significantly (p<0.001). The results of the present study showed usefulness of antimicrobial prophylaxis after normal delivery. As one of the factors, a significant decrease in the count of bacteria in lochia seems to contribute toward producing the satisfactory outcome.

Pharmacokinetic and bioequivalence comparison of a single 100-mg dose of cefteram pivoxil powder suspension and tablet formulations: a randomized-sequence, open-label, two-period crossover study in healthy Chinese adult male volunteers.

BACKGROUND: Cefteram pivoxil (CFTM-PI) is an oral antibiotic available in powder suspension and tablet formulations indicated in China for the treatment of bacterial infections. Although these 2 formulations are marketed in China, published information regarding their pharmacokinetics and bioequivalence in the Chinese population is not available. OBJECTIVE: The aim of this study was to compare the pharmacokinetics and bioequivalence of the powder suspension (test) and tablet (reference) formulations of CFTM-PI 100 mg available in China. METHODS: This single-dose, randomized-sequence, open-label, 2-period crossover study was performed at the Nanjing First Hospital of Nanjing Medical University. Eligible subjects were healthy male volunteers who were randomly assigned at a 1:1 ratio to receive a single 100-mg dose of the test or reference formulation, followed by a 1-week washout period and administration of the alternate formulation. The study drugs were administered after a 12-hour overnight fast. Plasma was assayed using a high-performance liquid chromatography method. For analysis of pharmacokinetic properties, including C(max), AUC from time 0 (baseline) to 6 hours (AUC(0-6)), and AUC from baseline to infinity (AUC(0-infinity)), blood samples were obtained at intervals over the 6-hour period after study drug administration. The formulations were considered bioequivalent if the log-transformed ratios of C(max) and AUC were within the predetermined equivalence range (80%-125%) as established by the US Food and Drug Administration (FDA). Tolerability was assessed by monitoring vital signs and laboratory tests (hematology, blood biochemistry, hepatic function, and urinalysis), and by questioning subjects about adverse events (AEs). RESULTS: Twenty-four Chinese male subjects (mean [range] age,24.2 [23-32] years;weight,64.3 [58-67] kg; height, 172 [167-185] cm) enrolled; all completed the study. No period or sequence effect was observed. The 90% CIs for the log-transformed ratios of C(max), AUC(0-6;), and AUC(0-infinity) were 96.5 to 120.1, 95.7 to 110.2, and 96.2 to 110.4, respectively (all, P>0.05). Similar results were found for the data without log-transformation. No AEs occurred or were reported during the study. CONCLUSIONS: In this small study in healthy Chinese adult male volunteers, a single 100-mg dose of the powder-suspension formulation was bioequivalent to a single 100-mg dose of the tablet formulation based on the US FDA's regulatory definition (rate and extent of absorption). Both formulations were well tolerated.

[The effect of preoperative topical antibiotics in cataract surgery].

PURPOSE: We studied whether topical antibiotics prevent endophthalmitis after cataract surgery. METHODS: Cefmenoxime hydrochloride (CMX) or artificial tears (AT) were randomly instilled 72 hours before surgery. Conjunctival swab samples were taken before the instillation of eye drops (1) and after the instillation of eye drops (2). Aqueous humor (3) was cultured intraoperatively. RESULTS: Positive cultures were found in the CMX group of eyes in 76.3% of (1) samples, 58.1% of (2) samples, and 6.0% of (3) samples. In the AT group of eyes, positive cultures were found in 78.6% of (1) samples, 63.8% of (2) samples, and 2.9% of (3) samples. CMX was not effective. In the CMX group of eyes, Staphylococcus epidermidis was found in 59 eyes of group (1), 5 eyes of group (2), and 0 eyes of group (3). In the AT group of eyes, S. epidermidis was found in 70 eyes of group (1), 26 eyes of group (2), and 1 eye of group (3). In the cases where S. epidermidis was decreased by CMX topical use Propionibacterium acnes was increased. CONCLUSIONS: There is a possibility that preoperative topical use of CMX can reduce S. epidermidis. On the other hand, it might increase P. acnes. Considering these results and the fact that there was no difference in effectiveness in the aqueous humor cultures, preoperative CMX topical use may not prevent postoperative endophthalmitis except for endophthalmitis due to S. epidermidis.

Effects of the quantity of water and milk ingested concomitantly with AS-924, a novel ester-type cephem antibiotic, on its pharmacokinetics.

The effect of the quantity of water ingested concomitantly with drugs, on the absorption of AS-924, a novel prodrug-type cephem antibiotic, was studied in five healthy adult volunteers by a cross-over method, using cefteram-pivoxil (CTER-PI) as the control drug. In addition, the effect of milk on the absorption of AS-924 was also investigated. The absorption of CTER-PI was significantly reduced when administered together with 30 ml of water compared with its absorption when administered together with 150 ml of water, whereas no such reduction was found in the case of AS-924. Ingestion of milk did not significantly affect the absorption of AS-924. These results confirm that absorption of AS-924 after oral administration is not likely to be affected by the quantity of water taken concomitantly with the drug, nor by milk.

Effect of antacid pretreatment on the pharmacokinetics of AS-924, a novel ester-type cephem antibiotic--comparison with cefteram-pivoxil.

The effect of pretreatment with ranitidine, an antacid, on the absorption of AS-924, a novel prodrug-type cephem antibiotic derived from ceftizoxime (CTIZ), was examined in eight healthy adult male volunteers by the cross-over method, using cefteram-pivoxil (CTER-PI) as the control drug. The C(max) and area under the concentration (AUC) values and cumulative urinary excretion rate (0-24 h) of cefteram (CTER) after administration of CTER-PI decreased by 32, 38 and 37%, respectively, in the ranitidine pretreatment group whereas those of AS-924 were not affected by the antacid. The urinary levels of pivaloyl-carnitine determined to evaluate the solubility of these antibiotics in the gastrointestinal tract suggested that this was not affected by ranitidine. These results indicate that the absorption of CTER-PI was affected by pretreatment with ranitidine largely due to inactivation of this antibiotic in the gastrointestinal tract at high pH rather than to a decrease in solubility. In contrast, isomerization of AS-924 was hardly induced by the elevation of pH, thus demonstrating that AS-924 was less likely to be affected by pretreatment with antacids.

[Pharmacokinetics of subconjunctivally injected drugs in the anterior segment of rabbit eyes].

We injected 12.5, 25, 50 and 100 microliters portions of a combined solution of 2.5% sodium fluorescein (FL), 2.5% cefmenoxim hemihydrochloride (CMX), and 0. 25% chloramphenicol (CP) subconjunctivally into rabbit eyes by various methods. Drug levels were monitored in the tears and aqueous humor and measured via high performance liquid chromatography. In the tear fluid, the concentrations of CP decreased more rapidly with time than FL and CMX. The drugs penetrated the rabbit's eyes better when injected subconjunctivally than when administered by sub-Tenon's injection. After subconjunctival injection through the eyelid, the drug concentration in the tears decreased with time in almost the same way as for injection through the conjunctival membrane. There was little difference between the presence and absence of a puncture hole in the conjunctiva. When the whole cornea was sealed with cyanoacrylate glue to block transcorneal absorption, the FL concentration in the aqueous humor was 30% of that in the control and the CP concentration was less than 10% of that in the control. About 70% of FL penetrating the eyes was derived from the transcorneal route but most of the CP was derived from the transcorneal route. FL in 1% or 0. 25% sodium hyarulonate (HA) and saline was injected subconjunctivally, and the concentrations of FL in the cornea and vitreous humor were measured. FL in 0.25% HA penetrated rabbit eyes better than that in 1% HA. These findings suggest that by dissolving the drug in an adequate concentration of HA solution, better penetration of drugs into the eye can be obtained.

[Clinical studies on cefteram pivoxil in pediatrics].

Cefteram pivoxil (CFTM-PI), a newly developed oral cephem antibiotic was administered to treat 16 children with various infections. The results were summarized as follows. 1. The clinical responses were "excellent" in 7, "good" in 5, "fair" in 3 and "poor" in 1, with 75.0% efficacy rate. 2. No side effects and no abnormal laboratory findings were observed.

[Pharmacokinetic studies on oral antibiotics in pediatrics. II. A pharmacokinetic study on cefteram pivoxil in pediatrics].

A pharmacokinetic study on cefteram pivoxil (CFTM-PI) granules and tablets for pediatric use was performed, and pharmacokinetic parameters were calculated using the one-compartment open model with a time lag. 1. Twelve school children were administered orally with CFTM-PI granules at a dose level of 3 mg/kg either at 30 minutes before meal or 30 minutes after meal on a crossover design, and serum concentrations and urinary excretion rates of CFTM were determined. Tmax, Cmax, T 1/2 and urinary excretion rate following the administration before meal were 1.3 +/- 0.1 hours, 1.35 +/- 0.11 micrograms/ml, 1.21 +/- 0.07 hours and 13.4 +/- 1.5%, respectively. Tmax, Cmax, T 1/2 and urinary excretion rate following the administration after meal were 2.9 +/- 0.3 hours, 1.08 +/- 0.09 microgram/ml, 1.72 +/- 0.26 hours and 23.3 +/- 2.2%, respectively. Earlier Tmax, higher Cmax and lower urinary excretion rate were observed when the drug was administered before meal than when administered after meal. 2. Six school children were administered orally with CFTM-PI granules at 30 minutes after meal at a dose level of either 3 mg/kg or 6 mg/kg on a crossover design, and serum concentrations and urinary excretion rates of CFTM were determined. Cmax at a dose level of 3 mg/kg was 1.50 +/- 0.26 microgram/ml, Cmax at a dose level of 6 mg/kg was 2.58 +/- 0.29 micrograms/ml. There existed dose response. 3. Eighteen school children, 10 younger children and 6 infants were administered orally with CFTM-PI granules at a dose level of 3 mg/kg at 30 minutes after meal, and serum concentrations and urinary excretion rates of CFTM were determined. Tmax in school children, younger children and infants were 2.8 +/- 0.3, 3.4 +/- 0.3 and 2.0 +/- 0.4 hours, respectively. Slightly earlier Tmax's were observed in infants than in other children. Cmax in school children, younger children and infants were 1.22 +/- 0.11, 1.03 +/- 0.12 and 0.94 +/- 0.15 micrograms/ml, respectively. It seemed slightly high in the older school children, younger children, infants. Although T 1/2 were nearly the same in all age groups, it seemed somewhat longer in school children than in others. Urinary excretion rates in school children, younger children and infants were 21.5 +/- 1.8, 19.3 +/- 2.0 and 7.6 +/- 0.1%, respectively. Obviously low excretion rates were observed in infants.(ABSTRACT TRUNCATED AT 400 WORDS)

[Clinical evaluation of cefteram pivoxil fine granules in pediatric infections].

Cefteram pivoxil (CFTM-PI), in fine granules, was studied in pediatric infections and the results obtained are summarized below. It is concluded that CFTM-PI fine granule is an effective drug for the treatment of pediatric infections. 1. The pharmacokinetics of CFTM-PI fine granules was studied in 7 patients (5 males, 2 females) whose ages ranged from 9 to 15 years. (1) In 2 patients, administered with the drug at a dose of 3 mg/kg in the fasting state, serum peak concentrations of CFTM at 2 hours after administration were 0.66 and 0.53 micrograms/ml, and T 1/2 were 1.40 and 1.32 hours, respectively. Urinary recovery rates in the first 8 hours were relatively low at 5.8 and 10.8%, respectively. (2) In 1 patient, the drug administered at a dose of 6 mg/kg in the fasting state, serum peak concentration of CFTM at 2 hours after administration was 3.0 micrograms/ml, T 1/2 was 2.16 hours, and urinary recovery rate in the first 8 hours was 13.8%. In another 2 patients, CFTM-PI administered at a dose of 6 mg/kg after meal, serum peak concentrations of CFTM at 4 hours after administration were 5.8 and 2.5 micrograms/ml, T 1/2 of the latter was 1.93 hours, and urinary recovery rates in the first 8 hours were 27.0 and 14.4%, respectively. (3) In yet another 2 patients, CFTM-PI tablets was administered at a dose level of 150 mg after meal. Serum peak concentrations of CFTM were 1.7 and 1.6 micrograms/ml at 2 hours and 4 hours after administration, respectively, T 1/2 of the former was 1.38 hours, and urinary recovery rates were 24.1 and 15.5%, respectively. 2. Clinical results CFTM-PI as fine granules was administered to 18 patients, and the following results were obtained. (1) 12 cases (6 males, 6 females) with their ages ranged from 3 months to 12 years were administered with the drug at a dose of 10 mg/kg/day, divided into 3 equal portions. Clinical efficacies were fair in 1 case with bronchopneumonia, good in 3 cases with bronchitis and in 4 cases with tonsillitis/pharyngitis, excellent in 1 and good in another with scarlet fever, and good in 1 and poor in another with urinary tract infection (UTI) (2) Six cases (4 males, 2 females) with their ages were 6 and 7 years were administered with CFTM-PI at a dose of 20 mg/kg/day divided into 3 equal portions. Clinical efficacies were good in 1 case with bronchopneumonia, 2 cases with bronchitis and 3 cases with tonsillitis/pharyngitis.

[Clinical evaluation of a combination treatment with cefmenoxime and cefsulodin of severe infections in leukemia and related disorders].

A combination of cefmenoxime (CMX) and cefsulodin (CFS) which has a broad spectrum on various bacteria including Pseudomonas aeruginosa was evaluated for severe infections associated with hematological malignancies. Seventy one patients were treated with the combination therapy. Among them, 57 patients were evaluable for the effectiveness. Fourteen patients were not evaluable because 10 patients were subjected to additional therapy such as gamma-globulin, interferon, radiation and pulse therapy of a large dose of methylprednisolone, 3 were prophylactically treated and the remaining one was a patient with disseminated bone marrow metastasis of prostatic cancer and not a patient with a hematologic malignancy. Excellent responses were obtained in 24 (42.1%) patients and good response in 12 (21.1%) patients, with a total rate of effectiveness of 63.2%. Three patients who were treated prophylactically and one patient who suffered from prostatic cancer with metastasis to bone marrow, were included in the final evaluation of side effects. Side effects were observed in only one patient (1/61, 1.6%). Mild neutropenia was identified in a patient of 78 years of age in 4 days after the combined regimen was started. Neutropenia disappeared soon after the cessation of the treatment. These results showed that a combination of CMX and CFS was an effective and safe regimen for the treatment of severe infections in patients with hematological disorders.

[Clinical studies on cefteram pivoxil in the treatment of respiratory infections].

Cefteram pivoxil (CFTM-PI), a new ester type cephem antibiotic, was administered at a daily dose of 600 mg to 81 patients with respiratory infections. They included 4 cases of laryngopharyngitis, 5 cases of tonsillitis, 26 cases of acute bronchitis, 13 cases of pneumonia, 10 cases of chronic bronchitis, 1 case of diffuse panbronchiolitis, 14 cases of infected bronchiectasis and 8 cases of infected other chronic respiratory diseases. Clinical effects were excellent in 18 cases, good in 50 cases, fair in 7 cases, and poor in 6 cases, thus, the efficacy rate was 84.0%. Nausea was observed in 2 cases, and diarrhea, vertigo, or fever was observed in 1 case each. The elevation of GOT and GPT values were found in 4 cases and a slight elevation of total bilirubin value was found in 1 case. These adverse reactions, however, were slight in their grades. CFTM-PI appears to be a useful oral cephem antibiotic in the treatment of respiratory infections.

[Effects of antacids on absorption, excretion and metabolism of cefteram pivoxil].

Effects of various antacids (sodium bicarbonate, aluminium hydroxide gel) and an H2-blocker (cimetidine) on the absorption and excretion of a new cephem drug for oral use, cefteram pivoxil (CFTM-PI), were studied in healthy adult volunteers. 1. No significant differences were found in serum levels of CFTM and CFTM-A (an inactive isomer of cefteram (CFTM)) or their urinary excretion levels (concentration, recovery rate) between the group given CFTM-PI in combination with sodium bicarbonate and that given CFTM-PI alone. 2. There were no significant differences in serum levels of CFTM and CFTM-A or their urinary excretion levels (concentration, recovery rate) between the group given CFTM-PI in combination with aluminium hydroxide gel and that given CFTM-PI alone. 3. In contrast, serum levels of CFTM and its urinary recovery rate were significantly less in the group given the drug in combination with cimetidine than in that given a single administration 2-3.5 hours and 2-4 hours after administration, respectively. Clinical considerations remain.

[Diffusion of cefmenoxime into prostatic fluid in the patients with acute bacterial prostatitis].

Expressed prostatic fluid (EPS) levels and serum levels of cefmenoxime (CMX) after intravenous administration were examined in 16 patients with acute bacterial prostatitis and 23 patients without prostatic diseases. Blood was drawn at 30, 60, 120 minutes and EPS was taken by prostatic massage at 60 minutes after the intravenous administration of 2 g CMX to evaluate the concentration of CMX. The concentration of CMX was determined by the bioassay using the E. coli NIHJ JC strain. The relationships between the EPS/serum ratio and peripheral WBC counts, CRP value and ESR 1h value were also analyzed. The serum levels of CMX at 60 minutes ranged between 20.3 micrograms/ml and 73.5 micrograms/ml (mean +/- S.D.: 41.8 +/- 14.2 micrograms/ml) in 16 patients with acute prostatitis, and between 21.5 micrograms/ml and 89.5 micrograms/ml (mean +/- S.D.: 49.5 +/- 18.7 micrograms/ml) in 23 patients without prostatic diseases. The EPS levels ranged between 0.4 micrograms/ml and 30.8 micrograms/ml (mean +/- S.D.: 12.6 +/- 9.6 micrograms/ml) in 16 patients with acute prostatitis, and between 0 and 2.3 micrograms/ml (mean +/- S.D.: 0.7 +/- 0.8 microgram/ml) in 19 patients without prostatic diseases. In 4 patients without prostatic diseases, the EPS amount was not large enough to evaluate the concentration of CMX. The EPS/serum ratio ranged between 0.006 and 0.697 (mean +/- S.D.: 0.31 +/- 0.21) in patients with acute prostatitis and between 0 and 0.058 (mean +/- S.D.: 0.015 +/- 0.018) in patients without prostatic diseases. The diffusion of CMX into the prostatic fluid in patients with acute prostatitis was strikingly higher than that in patients without prostatic diseases (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Elimination of cefmenoxime during continuous haemofiltration.

The elimination of cefmenoxime after single and repeated i.v. dosing was studied in 12 patients with severe renal failure and sepsis during continuous haemofiltration. More than 30% of the drug was found in the filtrate. The sieving coefficient (S) was 0.54. Vss% was unchanged 0.31 l.kg-1 in comparison with patients with normal renal function, whereas the mean t1/2ss was prolonged to about 16 h, and total clearance was reduced 20.8 ml.min-1.1.73 m-2. Once daily administration of 1 g cefmenoxime is suggested as the appropriate dose under such circumstances.