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Cefixime. A review of its antibacterial activity. Pharmacokinetic properties and therapeutic potential.

Cefixime, previously designated FK027, FR17027 and CL284635, is an orally active cephalosporin with a broad spectrum of antibacterial activity in vitro. It is particularly active against many Enterobacteriaceae, Haemophilus influenzae. Streptococcus pyogenes, Streptococcus pneumoniae and Branhamella catarrhalis, and is resistant to hydrolysis by many beta-lactamases. Cefixime has little activity against Staphylococcus aureus and is inactive against Pseudomonas aeruginosa. Cefixime is distinguished by its 3-hour elimination half-life which permits twice daily, or in many instances once daily, administration. Comparative trials, though few, indicate that the clinical and bacteriological efficacy of cefixime 200 to 400mg daily administered as a single dose or in 2 divided doses, is comparable with that of multiple daily doses of co-trimoxazole (trimethoprim + sulphamethoxazole) or amoxycillin in acute uncomplicated urinary tract infection, with that of amoxycillin, amoxycillin/clavulanic acid and cefaclor in acute lower respiratory tract infections, and with that of amoxycillin and cefroxidine in adult patients with acute tonsillitis or pharyngitis. Several comparative trials in children with acute otitis media demonstrate the similar effectiveness of cefixime 8 mg/kg daily (in 2 divided doses, or as a single daily dose), cefaclor 20 to 40 mg/kg daily and amoxycillin 40 mg/kg daily in 3 divided doses. The most frequently reported adverse effects, diarrhoea and stool changes, are usually mild to moderate in severity, transient, and mostly occur in the first few days of treatment with cefixime. Thus, cefixime is an effective orally active cephalosporin with a relatively long elimination half-life permitting a simplified treatment regimen. It is a suitable alternative to cefaclor or amoxycillin in acute otitis media and acute upper and lower respiratory tract infections, and to amoxycillin or co-trimoxazole in acute uncomplicated urinary tract infections.

Anti-Infective Agents↗

[Pharmacokinetic interaction of cefixime and 2 antacids. Preliminary results].

A crossover study was undertaken in 8 healthy volunteers to evaluate the pharmacokinetics of cefixime administered orally alone or combined with an antacid. Each subject received successively: cefixime alone, Maalox followed 30 min later by cefixime, then Maalox followed 4 hours later by cefixime and finally Alka-Seltzer followed 30 min later by cefixime. Sixteen blood samples were drawn from 0 to 24 hours after oral administration, and plasma cefixime parameters were determined, using a HPLC assay. Four parameters were used to detect a possible interaction: Cmax, Tmax, AUCO-N and AUCO-alpha. No significant difference was observed between the four parameters. Thus, poor absorption of cefixime when combined with an antacid can be ruled out.

Adult↗

[Comparative study of intravenous ceftriaxone followed by oral cefixime versus ceftriaxone alone in the treatment of severe upper urinary tract infections].

Cefixime is a new orally active cephalosporin. Its MICs and beta-lactamase stability are similar to those of the parenteral third generation cephalosporins. This trial was conducted to determine the effectiveness and safety of ceftriaxone as compared with a treatment where oral cefixime was given after a 4-day treatment with ceftriaxone in severe upper urinary tract infections usually requiring parenteral treatment during two weeks. In an open, controlled trial, 95 patients met the inclusion criteria; 48 received IV ceftriaxone 2 g daily during 4 days, followed by IM or IV ceftriaxone 1 g daily for 11 days; 47 patients were treated by IV ceftriaxone 2 g.o.d. during 4 days and then by oral cefixime 200 mg b.i.d. for 11 days. Clinical cure at the end of treatment was achieved in 44 patients in the cefixime group and 47 patients of the ceftriaxone group. Ten to 84 days after the end of treatment, the overall clinical cure and bacteriologic eradication rates for these patients were 74.3 per cent (29/39) for cefixime and 81 per cent (34/42) for ceftriaxone. Treatment failure occurred in two patients in the cefixime arm, one in a patient with renal atrophy and vascular stenosis and the other in an 86-year old diabetic and bed-ridden woman with an infection following the use of a urinary catheter. There were eight relapses or re-infections (about 20 per cent) in each group. Seven minor adverse events were seen in six patients treated with ceftriaxone: pain upon IM injection (3 cases), diarrhea (2 cases) associated in one case with a generalized rash for which treatment was discontinued, and nausea (one case). Laboratory changes in both groups were not noteworthy and without clinical relevance. These results suggest that it seems possible to propose new parenteral cephalosporins with conversion to the oral route on the 5th day using the same class of drugs in the treatment of severe upper urinary tract infections, excluding certain urological or vascular underlying conditions and provided that duration of treatment is adapted to the type of clinical setting. These data define more accurately the use of cefixime with respect to currently available drugs.

Administration, Oral↗

H+ coupled transport of p.o. cephalosporins via dipeptide carriers in rabbit intestinal brush-border membranes: difference of transport characteristics between cefixime and cephradine.

We demonstrated previously that aminocephalosporins, such as cephradine, possessing a alpha-amino group and a carboxyl group, are transported via H+/dipeptide carrier system in the intestinal brush-border membranes. The present study examined the transport characteristics of cefixime, a new p.o. cephalosporin with two carboxyl groups, by the rabbit intestinal brush-border membrane vesicles in comparison with those of cephradine. With an intravesicular pH of 7.5, apparent optimum extravesicular pH was 6.0 for cephradine uptake and more acidic (pH 4.5-5.0) for cefixime uptake. An inward H+ gradient [( pH]i = 7.5, [pH]o = 5.0) induced overshoot uptake of cefixime, and this uptake was reduced in the presence of carbonyl cyanide p-trifluoromethoxyphenylhydrazone, a protonophore. Cefixime uptake at pH 5.0 was trans-stimulated (countertransport effect) and cis-inhibited by dipeptides and aminocephalosporins but not at pH 7.5. Cephradine uptake at pH 7.5 was stimulated by the countertransport effect of dipeptide but not by cefixime. Cefixime and cephradine uptake at pH 5.0 was greatly inhibited by 4,4'-diisothiocyano-2,2'-disulfonic stilbene. These findings indicate that cefixime is transported by an inward H+ gradient via dipeptide carrier only in an acidic pH region, whereas cephradine is transported via dipeptide carrier in both neutral and acidic pH regions, suggesting the existence of multiple transport systems for dipeptides; a neutral pH preferring system (Type I) and an acidic pH preferring system (Type II).

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

Carrier-mediated transport of cefixime, a new cephalosporin antibiotic, via an organic anion transport system in the rat renal brush-border membrane.

The renal excretion mechanism of cefixime, a newly developed and p.o. effective cephalosporin antibiotic, was investigated by using the renal brush-border membrane vesicles from the rat kidney cortex. The initial uptake rate of cefixime into an osmotically sensitive vesicular space showed concentration and temperature dependencies, indicating the presence of a carrier-mediated transport mechanism for cefixime. Kinetic parameters for apparently saturable and nonsaturable components were evaluated as follows: maximum uptake rate was 7.32 +/- 1.07 nmol/30 sec/mg of protein; Michaelis constant was 7.35 +/- 2.04 mM; and the first-order rate constant was 0.34 +/- 0.02 nmol/30 sec/mg of protein per mM. The uptake was not affected by an inward-directed gradient of Na+, K+, Li+, Rb+ or H+. In contrast, the initial uptake rate was enhanced by an inside-positive membrane potential imposed by valinomycin. Although amino acids, dipeptides and organic cations had no effects on the uptake of cefixime, organic anions such as probenecid and p-aminohippuric acid and anion transport inhibitors such as 4,4'-diisothiocyano-stilbene-2,2'-disulfonic acid and furosemide reduced the uptake significantly. Twenty beta-lactam antibiotics including both zwitter-ionic and anionic derivatives inhibited significantly the uptake of cefixime. Furthermore, by adding probenecid in the extravesicular medium, an efflux of cefixime from the brush-border membrane vesicles was enhanced significantly at the initial stage. Benzylpenicillin, cephalothin and cephradine also enhanced an efflux of cefixime to the same extent as observed by the addition of probenecid.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Interpretation of middle ear fluid concentrations of antibiotics: comparison between ceftibuten, cefixime and azithromycin.

AIMS: The aim of this study was to determine the potential influence of variables such as the cell content in the fluid, and serum levels, on the concentrations of ceftibuten, cefixime and azithromycin in the middle ear fluid of patients suffering from acute otitis media. METHODS: This randomized, open study compared the penetration of ceftibuten (9 mg kg(-1) 18 patients), cefixime (8 mg kg(-1), 16 patients) and azithromycin (10 mg kg(-1) 16 patients) into the intracellular and extracellular compartments of middle ear fluid of 50 paediatric patients (aged 8-14 years) with acute otitis media. Middle ear fluid was extracted by tympanocentesis 4, 12 and 24 h after dosing and divided into two fractions: with cells (as collected) (C+) and cell-free (C-). Antibiotics were assayed in C+ and C- samples by h.p.l.c. RESULTS: Ceftibuten achieved greater penetration into middle ear fluid than cefixime and azithromycin. Higher concentrations of ceftibuten (CTB) and cefixime (CFX) were found in the C- fraction (CTB: 4h 13.3+/-1.86; 12h 4.7+/-1.18; 24h 0.5+/-0.2. CFX: 4h 3.2+/-1.4; 12h 1.5+/-0.5; 24h>(0.1 mgl(-1)) than in the C+ fraction (CTB:4 h 8.4+/-4.3; 12 h 2.88+/-1.19; 24 h 0.3+/-0.27. CFX: 4 h 1.2+/-0.6; 12 h 0.8+/-0.2; 24 h>0.1 mg l(-1)) at the each time point, while the opposite was true for azithromycin (C-: 4 h 0.11+/-0.04; 12 h 0.12+/-0.08; 24 h 0.23+/-0.12. C+: 4 h 0.38+/-0.24; 12 h 0.9+/-0.03; 24 h 1.05+/-0.3 mg l(-1)). CONCLUSIONS: This study demonstrates that the penetration of antibiotics into the middle ear fluid is influenced by its serum concentrations as well as by the cell content in the fluid. Ceftibuten achieved higher middle ear fluid concentrations than cefixime in C+ and C- fractions at all time points. Both ceftibuten and cefixime concentrations are negatively influenced by the cell content in the fluid. In contrast the concentration of azithromycin to the middle ear fluid is positively influenced by the cell content in the fluid.

Acute Disease↗

Parameters characterizing the in vitro activity of cefixime, a new oral broad spectrum cephalosporin, against respiratory and urinary pathogens.

The wide and potent in vitro activity of cefixime, a new oral broad spectrum cephalosporin, has been confirmed on a collection of respiratory and urinary pathogens recently isolated in Italy. The new cephem emerged as the most bactericidal of all the comparators tested against several fast as well as slowly-growing gram-negative species including Enterobacteria, Haemophilus and Moraxella, irrespective of their ability to synthetize beta-lactamases. Among the gram-positive species Streptococcus pyogenes and S. pneumoniae were effectively covered. Cefixime activity was not adversely influenced by several important variables such as pH (over the range from 5 to 8), inoculum size (from 10(5) to 10(8) CFU per ml) and the presence of 50% human serum or urine. Time-kill tests confirmed a pronounced bactericidal potency of the drug especially towards common respiratory pathogens (H. influenzae, M. catarrhalis, S. pneumoniae and S. pyogenes). Killing of urinary strains was optimal at cefixime concentrations reached in urine since eradication, except for Proteus mirabilis, was enhanced with increasing levels of the drug. The absence of an untoward paradoxic effect on the rate of cefixime bactericidal action was confirmed by employing a dynamic bladder model simulating the pharmacokinetic parameters of the drug after a single 200 mg daily dosage. Interactions of cefixime with several other drugs that may be employed in combination therapy were generally prone to provide indifference and synergism while antagonism was never observed. Favorable interactions were also registered when cefixime acted with other antibiotics on partially resistant species such as Staphylococci and Pseudomonas. The new cephem seems to provide excellent opportunities for expanding oral cephalosporin therapy to a wide range of infections produced by susceptible pathogens in the adult and pediatric populations.

Anti-Infective Agents, Urinary↗

Comparison of roxithromycin with cefixime in the treatment of adults with community-acquired pneumonia.

This study compared the efficacy and tolerability of once-daily dosing with either roxithromycin or cefixime in previously healthy adult patients aged between 18 and 60 with markers of uncomplicated community-acquired pneumonia (CAP) in three outpatient clinics in an open, randomized study. Sixty patients were enrolled: 17 males and 13 females received roxithromycin 300 mg once daily for 8-10 days and 22 males and eight females received 400 mg cefixime once daily for the same period. All patients were assessed clinically, radiologically and bacteriologically before inclusion, immediately after the study and approximately 1 month later. The most common pathogen isolated from sputum was Streptococcus pneumoniae (in 26 (43%) of 60 patients), with mixed organisms isolated from the sputum of 18 (30%) of 60 patients. Staphylococcus aureus, Haemophilus influenzae or Moraxella catarrhalis occurred in 11/60 patients, and atypical pathogens were detected by serology in 7/26 cases in the roxithromycin group and 3/23 in the cefixime group. The severity of infection was rated as mild to moderate at the beginning of the trial. At the end of the study treatment period, clinical cure rates were 30/30 (100%) for roxithromycin and 28/30 (94%) for cefixime, with one patient on cefixime being classed as a partial responder and one patient being classed as a failure and withdrawn. However, radiological abnormalities persisted in three patients on roxithromycin and one on cefixime. Of the 59 patients who completed the study, none required further antibiotic therapy. No abnormal laboratory parameters or adverse events were reported in either group. Roxithromycin at a daily dose of 300 mg was an effective and well-tolerated treatment for the empirical treatment of mild to moderate CAP in this group of patients.

Adolescent↗

Microbiologic and clinical aspects of a trial of once daily cefixime compared with twice daily cefaclor for treatment of acute otitis media in infants and children.

In this randomized, investigator-blinded multicenter study, tympanocentesis for acute otitis media with effusion in 137 ears from 108 children, 6 months to 12 years of age, revealed 84 definite pathogens and 32 potential pathogens. Twenty-nine aspirates from 23 subjects were sterile. Of the 116 isolates 42 (36%) were Streptococcus pneumoniae, 24 (21%) were Haemophilus influenzae, 9 (8%) were Moraxella catarrhalis, 9 (8%) were Streptococcus pyogenes and 1 (1%) was Staphylococcus aureus. Twenty-two (19%) definite pathogens produced beta-lactamase. Patients were randomized to cefixime (8 mg/kg/day daily) or cefaclor (40 mg/kg/day divided into two doses). Efficacy was determined by pneumatic otoscopy and tympanometry at the end of therapy visit on Days 11 to 14 and up to 4 weeks of follow-up. At end of therapy subjects with definite pathogens exhibited a satisfactory clinical outcome in 26 of 36 (72%) ears for cefaclor and 40 of 48 (83%) ears for cefixime recipients (P = 0.12). For ears with beta-lactamase-producing isolates there were no (0 to 12) cefixime failures but 4 of 10 cefaclor failures (P = 0.03). Diarrhea/loose stools were more frequent in cefixime (16 of 58) than cefaclor (4 of 50) recipients. One cefixime subject required discontinuation of drug. Overall efficacy for treatment of acute otitis media with effusion was not different; however, cefixime appeared more effective for infections caused by beta-lactamase-producing organisms.

Acute Disease↗

A comparative study of ofloxacin and cefixime for treatment of typhoid fever in children. The Dong Nai Pediatric Center Typhoid Study Group.

BACKGROUND: Despite concerns about safety in children, fluoroquinolone antibiotics have become the treatment of choice in patients with multidrug-resistant typhoid fever in Vietnam. However, quinolone-resistant strains of Salmonella typhi have recently been reported from Vietnam; and if quinolone resistance becomes established, alternative oral treatment options will be needed. OBJECTIVE: Cefixime, an orally administered third generation cephalosporin, was compared with ofloxacin for the treatment of uncomplicated typhoid fever in children. METHODS: In an open trial children with suspected typhoid fever were randomized to receive either ofloxacin (10 mg/kg/day in two divided doses) for 5 days or cefixime (20 mg/kg/day in two divided doses) for 7 days. RESULTS: S. typhi was isolated from 82 patients (44 in the cefixime group, 38 in the ofloxacin group) and 70 (85%) of the isolates were multidrug-resistant. Median (95% confidence interval, range) fever clearance times were 4.4 (4 to 5.2, 0.2 to 9.9) days for ofloxacin recipients and 8.5 (4.2 to 9, 1.8 to 15.2) days for cefixime-treated patients (P < 0.0001). There were 11 treatment failures (10 acute and one relapse) in the cefixime group and 1 acute treatment failure in the ofloxacin group (mean difference, 22%; 95% confidence interval, 9 to 36%). CONCLUSION: Short course treatment with cefixime may provide a useful alternative treatment in cases of uncomplicated typhoid fever in children, but it is less effective than short course treatment with ofloxacin.

Adolescent↗

Pharmacokinetics and cerebrospinal fluid concentrations of cefixime in infants and young children.

Limited data are available about cefixime pharmacokinetics and cerebrospinal fluid (CSF) penetration in infants and young children. Ten patients with bacterial meningitis and 8 undergoing CSF shunt placement, aged 2-22 months (mean 9.5 +/- 6.5 months), were given a single dose of cefixime suspension, 8 mg/kg, before undergoing a routine lumbar puncture. Patients were fasted for 2 h before and 2 h after drug administration. Blood samples were collected just before drug administration (0 h) and at 1, 2, 3, 4, 6, 8 h; CSF was obtained at 1-8.8 h after drug administration. Cefixime was measured by a high-performance liquid chromatographic method. The peak serum concentration of cefixime ranged from 0.85 to 6.2 (mean 3.1) micrograms/ml and occurred at 2-8 h (mean 4.5). The area under the serum concentration-time curve ranged from 5.3 to 28.4 micrograms h/ml, and the elimination half-life ranged from 2.6 to 5.6 h. CSF concentrations ranged from 0.02 to 0.57 micrograms/ml. The mean CSF concentration of cefixime was 0.22 micrograms/ml in patients with meningitis and 0.10 microgram/ml in those undergoing shunt placement (p < 0.02). The mean CSF concentration/serum concentration ratio was 11.7 in patients with meningitis compared with 5.4 in those undergoing shunt procedures (p < 0.02). These data indicate that cefixime can be considered as an alternative to other antimicrobials for infants and children with respiratory and urinary tract infections, since the observed peak serum concentration exceeded the minimum inhibitory concentrations of the common pathogens by severalfold.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Infective Agents↗

Cefixime. A review of its therapeutic efficacy in lower respiratory tract infections.

Cefixime is an orally active third generation cephalosporin with in vitro antibacterial activity against most important lower respiratory pathogens. The drug is active against Haemophilus influenzae, Moraxella catarrhalis and penicillin-susceptible Streptococcus pneumoniae but not Staphylococcus aureus. Cefixime has a long elimination half-life (3 hours compared with 0.5 hours for cefaclor and 1.5 hours for cefalexin), which allows once daily administration. Several trials have established the clinical efficacy of the drug in patients with lower respiratory tract infection (LRTI). In comparative studies cefixime had similar efficacy to amoxicillin +/- clavulanic acid, cefaclor, cefalexin, cefuroxime axetil and clarithromycin. Trials evaluating the efficacy of cefixime as the oral component of intravenous to oral switch therapy have produced promising preliminary results although further carefully designed trials are needed in this area. As with certain other drugs of its class, gastrointestinal disturbances are the most frequently reported adverse events in patients taking cefixime and cases of pseudomembranous colitis have been reported. Thus, cefixime is an effective treatment for mild to moderate LRTI and may have a role as the oral component of intravenous to oral switch therapy although further well designed studies are needed to confirm initial favourable results in this important emerging area of antibacterial therapy.

Anti-Bacterial Agents↗

Impact of cefixime on the normal intestinal microflora.

The ecological effects on the normal intestinal microflora after cefixime tablets in doses of 200 mg twice daily for 7 days were studied in 10 healthy volunteers. Stool specimens were collected before and 2, 4, 7, 14 and 21 days after start of treatment. Plasma samples were collected during 12 h after the first dose on day 1 and 1 sample was taken on day 7 for bioassay of cefixime concentration. Peak plasma concentration of cefixime occurred after about 4 h with a mean of 3.0 mg/l. The mean AUC0----oc after a single dose was estimated at 21.9 mg x h/l and the mean elimination half-life was 3.9 h. The mean plasma concentration of cefixime 3 h after the morning dose on day 7 was 2.0 mg/l. The concentrations of cefixime in faeces increased during treatment. One subject had detectable concentrations in faeces on day 2, three subjects on day 4 and 8 subjects on day 7 in the order of 237-912 mg/kg faeces. There was a marked decrease in the numbers of streptococci and Escherichia coli and an increase in the numbers of enterococci during the administration of cefixime. In the anaerobic microflora, the numbers of cocci, clostridia and bacteroides were suppressed while there were minor changes in the numbers of bifidobacteria. Clostridium difficile was isolated in 5 subjects on day 7 but cytotoxin was only detected in one subject. The intestinal microflora was normalized within 2 weeks after treatment had stopped. Slightly soft stools were reported by 7 subjects. One subject had abdominal pain and diarrhoea 1 week after treatment followed by anal irritation and itching.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

Susceptibility of respiratory tract pathogens in Finland to cefixime and nine other antimicrobial agents.

The in vitro activity of cefixime and 9 other orally used antimicrobial agents against 545 selected clinical respiratory tract pathogens was tested using the plate-dilution method. Of the strains tested, 144 were Haemophilus influenzae strains, 151 group A streptococci, 105 pneumococci and 145 Moraxella catarrhalis isolates. Ciprofloxacin was the most active drug, with a minimal inhibitory concentration (MIC) of < 0.06 mg/l for more than 87% of the isolates. With cefixime, a MIC of 0.06 mg/l inhibited 55% of the strains tested and a MIC of 1.0 mg/l inhibited all except one of the 545 strains. One pneumococcal strain was resistant to cefixime. Beta-lactamase producing H. influenzae and M. catarrhalis strains were clearly more susceptible to cefixime than to other oral cephalosporins (cephalexin, cefaclor, cefuroxime). However, penicillin, ampicillin and cefuroxime were more effective against beta-hemolytic streptococci and pneumococci than was cefixime. The new third generation cephalosporin, cefixime, showed markedly better in vitro activity against certain major respiratory tract pathogens than the other peroral antimicrobials commonly used against respiratory tract infections.

Anti-Bacterial Agents↗

Treatment of shigellosis: IV. Cefixime is ineffective in shigellosis in adults.

OBJECTIVE: To compare the efficacy of cefixime with that of pivamdinocillin in the treatment of adults with acute dysentery caused by Shigella infection. DESIGN: Randomized, double-blind clinical trial. SETTING: A diarrhea treatment center in Dhaka, Bangladesh. PATIENTS: 30 men with dysentery lasting 72 hours or less. INTERVENTIONS: Patients were randomly assigned to receive either 400 mg of cefixime every 24 hours (n = 15) or 400 mg of pivamdinocillin every 6 hours (n = 15) for 5 days. All patients were hospitalized for 6 days. Patients in whom initial drug therapy failed received alternative antimicrobial therapy. MEASUREMENTS: Physical examinations were done and symptoms were recorded daily, and body temperatures were measured every 6 hours. Stools were counted and examined for consistency and for the presence of blood and mucus. Therapy failed if symptoms of dysentery persisted for more than 72 hours or if, on study day 5, a patient had six stools, one watery or bloody-mucoid stool, or an oral temperature higher than 37.8 degrees C. Bacteriologic failure of therapy occurred if Shigella could be isolated from a stool sample on or after study day 3. RESULTS: Therapy failed in seven (47%) patients given cefixime but in none of the patients given pivamdinocillin (P = 0.006). Patients given cefixime had longer duration of fever (median, 6 hours compared with 0 hours, P = 0.019), longer duration of the period with dysenteric stools (median, 4 days compared with 1 day, P = 0.001), and more stools during the 6 study days (median, 65 compared with 28, P = 0.002) than patients treated with pivamdinocillin. Bacteriologic failure of therapy occurred in 60% of patients (9 of 15) given cefixime and 13% of those (2 of 15) given pivamdinocillin (P = 0.009). CONCLUSION: Cefixime is ineffective in treating shigellosis in adults when used in the standard recommended dosage.

Adolescent↗

Spectrophotometric, difference spectroscopic, and high-performance liquid chromatographic methods for the determination of cefixime in pharmaceutical formulations.

Three simple and sensitive spectrophotometric, difference spectroscopic, and liquid chromatographic (LC) methods are described for the determination of cefixime. The first method is based on the oxidative coupling reaction of cefixime with 3-methyl-2-benzothiazolinon hydrazone HCI in presence of ferric chloride. The absorbance of reaction product was measured at the maximum absorbance wavelength (wavelength(max)), 630 nm. The difference spectroscopic method is based on the measurement of absorbance of cefixime at the absorbance maximum, 268 nm, and minimum, 237 nm. The measured value was the amplitude of maxima and minima between 2 equimolar solutions of the analyte in different chemical forms, which exhibited different spectral characteristics. The conditions were optimized, and Beer's law was obeyed for cefixime at 1 to 16 microg/mL and 10 to 50 microg/mL, respectively. The third method, high-performance LC, was developed for the determination of cefixime using 50 mM potassium dihydrogen phosphate (pH 3.0)-methanol (78 + 22, v/v) as the mobile phase and measuring the response at wavelength(max) 286 nm. The analysis was performed on a Lichrospher RPC18 column. The calibration curve was obtained for cefixime at 5 to 250 microg/mL, and the mean recovery was 99.71 +/- 0.01%. The methods were validated according to the guidelines of the U.S. Pharmacopoeia and also assessed by applying the standard addition technique. The results obtained in the analysis of dosage forms agreed well with the contents stated on the labels.

Anti-Bacterial Agents↗

[Antibacterial effect of cefixime in the presence of the type of beta-lactamases produced by Enterobacteriaceae].

The susceptibility of isolates or Enterobacteriaceae to orally absorbed beta-lactams (amoxicillin, cephalexin, cefaclor, cefuroxime, and cefixime), was maximum for the iminomethoxy-aminothiazolyl-cephalosporin but variable according to bacterial species. For E. coli, P. mirabilis, Salmonella, Shigella, K. pneumoniae, K. oxytoca (group 1) MIC50 were congruent to 0.06 mg/l, and MIC90 congruent to 0.12 mg/l. Finally for C. freundii, E. aerogenes, E. cloacae, S. marcescens, M. morganii, MIC50 were higher, congruent to 1, and MIC90 16 mg/l. The slight increase reported between MIC50 ans MIC90 of cefixime against isolates belonging to group 1 was related to stability towards beta-lactamases (TEM, SHV) unlike groups 2 and 3, where the drug was less stable to chromosomal type 1 enzyme. The discovery of extended-spectrum beta-lactamases (ESB) (e.g. SHV-2, CTX-1 or TEM-3), mainly in K. pneumoniae, led to further investigations of the behavior of cefixime. The in vitro activity of cefixime (CFM), amoxicillin (AMX) combined or not with clavulanate (AMC, 2 mg/l), ticarcillin (TIC), cephalothin (CF), cefotaxime (CTX), ceftazidime (CAZ) and aztreonam (AZM) was determined by the agar dilution method (inoculum 10(5) cfu/ml) against clinical isolates: E. coli (26), K. pneumoniae (42), K. oxytoca (9), Salmonella (3) producing several types of beta-lactamases, chromosomal (cephalosoporinase, broad-spectrum) or plasmid-encoded (TEM-1, TEM-2, CTX-1, SHV-2, SHV-3, SHV-4). The geometric mean MIC values of AMX, AMC, TIC, CF, CTX, CAZ, AZM and CFM were as follows: greater than 480, 21.6, greater than 285, 45.6, 0.53, 1.12, 0.51, and 0.77 respectively. An MIC increase of oxyimino beta-lactams (CTX, CAZ, AZM, CFM) was observed against over-producing isolates of K. oxytoca and isolates producing ESB (CTX-1, SHV-2, SHV-3, SHV-4). The comparative behavior of cefixime was determined after transfer by conjugation to E. coli K-12. Sixty-one derivatives were constructed producing TEM-1, TEM-2, SHV-1, CTX-1, TEM-4, CAZ-2, SHV-2, SHV-3, SHV-4, the MICs of cefixime were stable against derivatives producing a penicillinase (TEM-1, TEM-2, SHV-1), but not against those producing an ESB. The MIC increases of undigestible beta-lactams ranged from 1 to 135 fold (CFM), 40 to 200 fold (CTX) 12 to 232 fold (CAZ), and 4 to 240 fold (AZM).

Anti-Bacterial Agents↗

[Tonsil diffusion of cefixime in children].

Cefixime is a new oral cephalosporin antibiotic, with broad-spectrum of activity, near than of third generation cephalosporin, especially against betelactamase producers bacteria. Cefixime has been assayed with microbiological method in tonsils of 21 children (mean age 59 months). Tonsillectomy was performed 5 hours after a third dose of 4 mg/kg cefixime. Plasma levels were evaluated 10 hours after the second dose, with mean level of 0.84 micrograms/ml (0 to 1.35). Blood level was evaluated after third dose, during amygdalectomy was 1.24 micrograms/ml (0.1 to 3.9). Tonsils levels were: for right tonsils 0.74 micrograms/g and for left tonsils 0.53 micrograms/g. Cefixime was not detected in both tonsils of 6 children, and in one of the two tonsils in 11 of them. The tonsils penetration of cefixime was about 1 microgram/g in the case where cefixime was detectable. This penetration is not regular as for other betalactam antibiotics in relation with fibrosis of tonsils tissue inhibiting a good diffusion of antibiotic.

Cefixime↗