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.

[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.

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.

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.

Intracameral levels of intravenously injected fluorescein, cefmenoxime, and chloramphenicol in the prostaglandin E2-administered eyes of albino rabbits.

We evaluated the effects of inflammation and physicochemical nature of selected agents on the intracameral levels of intravenously injected drugs in albino rabbits. Transcorneal diffusion of prostaglandin E2 (10, 50 or 250 micrograms/ml) using a glass cylinder was used to produce inflammation of the anterior segment in the right eyes. As a control, a vehicle was applied to the left cornea. Immediately, 2, 5, or 11 h after prostaglandin E2 administration, a mixed solution of fluorescein, cefmenoxime, and chloramphenicol (50 mg each/kg body weight) was injected intravenously. One hour after injection of the drugs, the primary aqueous humor was withdrawn. The intracameral levels of protein and these drugs after prostaglandin E2 administration increased at 1 h in a dose-dependent manner. These levels then gradually decreased. One hour after prostaglandin E2 administration, the intracameral levels of protein and these drugs in the prostaglandin E2-administered eyes were significantly higher than those in the vehicle-administered eyes, except chloramphenicol after administration of 10 micrograms/ml prostaglandin E2. Our findings indicate that the intracameral levels of intravenously administered drugs are altered not only by the severity of inflammation but also by the properties of drugs.

AUIC--a general target for the optimization of dosing regimens of antibiotics?

OBJECTIVE: To present a systematic evaluation of the are under the inhibitory curve (AUIC) approach for the optimization of antibiotic dosing schedules for three major antibiotic classes (beta-lactams, quinolones, aminoglycosides). It has been proposed that an AUIC over 24 hours of at least 125 may be an applicable target parameter for the optimization of antibiotic dosing schedules across these antibiotic classes. Some limitations of this approach are presented and discussed. METHODS: A precise equation for the calculation of AUIC is derived. Moreover, a specific equation is derived for the situation that results in a trough concentration at the end of the dosing interval equal to the minimum inhibitory concentration (MIC). With the same three drugs used for deriving the target AUIC value (tobramycin, cefmenoxime, ciprofloxacin), different dosing regimens are simulated to obtain the target AUIC of 125. RESULTS: Very different serum concentration profiles can result in the same AUIC. In an example for cefmenoxime, dosing regimens of 1 g q6h and 4.2 g q24h resulted in equal AUIC values of 125, whereas the respective time above MIC differed dramatically (99% of the dosing interval for q6h vs. 36% for q24h). CONCLUSIONS: It does not seem valid to accept the proposed breakpoint AUIC target of at least 125 as an applicable value for determining the appropriate dosing schedule of these classes of antibiotics. Based on the limitations discussed about the AUIC approach, the same conclusion also holds for any other fixed AUIC breakpoint target value.

[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.

Pharmacoeconomic analysis of cefmenoxime dual individualization in the treatment of nosocomial pneumonia.

OBJECTIVE: To determine if dual individualization of cefmenoxime dosing is cost-effective. DESIGN: Retrospective, pharmacoeconomic decision analysis of two consecutively conducted prospective clinical studies. PATIENTS: Patients with documented gram-negative nosocomial pneumonia were evaluated. Thirty-three patients received cefmenoxime at standard dosing and 28 patients received doses according to dual individualization methodology. MAIN OUTCOME MEASURE: Antibiotic and infection-related costs were compared between groups. The number of hospital antibiotic days and costs incurred on those days were also evaluated. A decision model was constructed to characterize differences in treatment outcome. Probabilities within the decision tree were derived from 61 evaluable patients. Cost-effectiveness and incremental cost-effectiveness ratios were calculated. Sensitivity analysis was performed by varying outcome probabilities, antibiotic prices, and hospital room costs. RESULTS: Antibiotic and infection-related costs (mean +/- SEM) were $848 +/- 78 for standard cefmenoxime dosing and $1123 +/- 128 for dual individualization (p < 0.05). Total hospital costs were $10,660 +/- 1432 for standard dosing and $11,709 +/- 1900 for dual individualization (p > 0.05). Median antibiotic length of stay (ALOS) was 15.2 and 12.7 days for standard and dual individualization methodologies, respectively (p > 0.05). Incremental analysis of cost-effectiveness indicated that a similar reduction in length of stay for 259 dual individualization patients would save $321,808 annually. CONCLUSIONS: Sensitivity analysis indicates that, by reducing ALOS, dual individualization could be a cost-effective method of beta-lactam dosing for patients with pneumonia. A prospective study should be conducted to validate these findings.

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.

Synergistic effects of romurtide and cefmenoxime against experimental Klebsiella pneumonia in mice.

We investigated the synergistic effects of romurtide (MDP-Lys [L18]) and cefmenoxime (CMX) in the treatment of experimental Klebsiella pneumonia in mice. Mice were infected with 1 x 10(4) CFU of Klebsiella pneumoniae by inhalation of aerosol bacterial suspension. About 90% of untreated animals died within a week; however, the mortality rate of animals treated with CMX alone at a dose of 40 mg/kg/day was 60% at 7 days after the infection. When one or two doses of L18 were administered before or after the infection concomitantly with CMX, a remarkable improvement in the survival rate was observed. There was no significant improvement in the survival rate of animals treated with L18 alone before or after infection. Histopathological sections of the lungs of mice treated with CMX and L18 showed slower progression of infection than those of mice treated with CMX alone. Significant differences were also found in quantitative cultures of viable bacteria in the lungs 1 to 4 days after the infection. Although viable bacterial counts in the lungs of the control and CMX-treated groups showed a rapid increase 24 to 48 h after the infection, they remained lower than the initial counts (x 10(4)) in the lungs of mice treated with combination regimens. From these results, it can be concluded that L18 is a useful biological response modifier in the treatment of acute pulmonary bacterial infections.

Application of mathematical model to multiple-dose experimental chemotherapy for fatal murine pneumonia.

Two beta-lactam antibiotics, cefazolin and cefmenoxime, were administered for 7 days to mice with pneumonia caused by Klebsiella pneumoniae by using dosage regimens that would simulate multiple dosing in usual clinical treatments at dosing intervals of 8 or 12 h. Viable numbers of the bacteria in the lungs were measured at 12- or 24-h intervals. The mathematical model established in a previous single-dose study was applied in this study to explain the time courses of the changes in bacterial count over 7 days. However, because the error in viable count measurements was larger than that in the previous study, the time course of the changes in mean viable count was not regular and the viable count reduction rate changed during multiple dosing, and therefore it was difficult to explain the time course by repeated application of the mathematical model described previously. This study suggests that the changes in pharmacokinetic and pharmacodynamic parameters during multiple dosing need to be considered.