Cefpodoxime proxetil. An appraisal of its use in antibacterial cost-containment programmes, as stepdown and abbreviated therapy in respiratory tract infections

Cefpodoxime proxetil is an orally administered prodrug which is converted in vivo to the third generation cephalosporin cefpodoxime. Cefpodoxime has a similar spectrum of antibacterial activity to the parenteral cephalosporins ceftriaxone and cefotaxime and a long elimination half-life, which allows once- or twice-daily administration. Cefpodoxime proxetil has proven efficacy in the treatment of community-acquired pneumonia and upper respiratory tract, skin and soft tissue and urinary tract infections. It has been evaluated for use in cost-containment programmes, as stepdown (parenteral-to-oral conversion) therapy in the treatment of community-acquired pneumonia and as abbreviated therapy in upper respiratory tract infections. Substituting oral for parenteral therapy can achieve considerable savings (in acquisition, delivery and labour costs). Moreover, oral administration has advantages for the patient in terms of comfort and mobility, avoids the hazards of parenteral delivery and may allow earlier discharge from hospital, or even allow home treatment from the outset in low-risk patients. As hospitalisation is usually the major cost component in treating serious infections, considerable savings can be made in this way. Pharmacy-driven stepdown programmes in 2 US hospitals have achieved cost savings by targeting patients with community-acquired pneumonia for early conversion from intravenous ceftriaxone therapy to oral cefpodoxime proxetil. Costs were compared with those from a control group of patients who continued to receive intravenous ceftriaxone until physicians deemed that oral therapy (with various agents) was appropriate. In one study, duration of parenteral therapy in the cefpodoxime proxetil group was reduced from 6.18 to 3.82 days and duration of hospitalisation was reduced from 10.06 to 6.23 days (p < 0.02), with corresponding hospitalisation cost reductions of $US7300 per patient. However, clinical trial data relating to the efficacy of cefpodoxime proxetil as stepdown therapy in patients initially requiring parenteral antibacterials are lacking. Abbreviated (4-to 7-day) cephalosporin regimens appear to be as effective as traditional 10-day penicillin regimens in the treatment of upper respiratory tract infections. Short regimens may improve patient compliance and tolerability, thereby reducing the costs of adverse effects and treatment failures. Data from preliminary clinical studies suggest that a 5-day course of cefpodoxime proxetil is as effective as an 8-day course of amoxicillin/clavulanic acid in treating either acute otitis media or sinusitis, and as effective as a 10-day course of amoxicillin/ clavulanic acid and more effective than a 10-day course of phenoxymethyl- penicillin in the treatment of pharyngotonsillitis. Cefpodoxime proxetil tended to be better tolerated and was associated with better compliance than penicillin-based regimens. Indeed, a pharmacoeconomic study showed that a 10-day regimen of cefpodoxime proxetil was associated with lower costs for treating adverse effects and treatment failures than a 10-day regimen of amoxicillin/clavulanic acid in the treatment of acute otitis media in children. A 5-day course of cefpodoxime proxetil had a lower cost per patient treated per month free of recurrence than a 10-day course of phenoxymethylpenicillin (non-generic) or amoxicillin/clavulanic acid in the treatment of recurrent pharyngotonsillitis. Thus, evidence to date suggests that cefpodoxime proxetil has potential for use as stepdown therapy in community-acquired pneumonia and in abbreviated therapy courses in upper respiratory tract infections. These preliminary observations require confirmation in well designed studies.     

Cefpodoxime proxetil: a review of its use in the management of bacterial infections in paediatric patients

Cefpodoxime proxetil is an oral third generation cephalosporin with a broad spectrum of antibacterial activity. The drug has in vitro activity against many common Gram-positive and Gram-negative pathogens associated with common paediatric infections, making the drug a useful option for empirical therapy. In randomised controlled trials conducted in children with acute otitis media, oral cefpodoxime proxetil 8 to 10 mg/kg/day (usually administered in 2 divided doses) for 5 to 10 days was at least as effective as standard regimens of amoxicillin/ clavulanic acid, cefixime, cefuroxime axetil or cefaclor as assessed by either clinical or bacteriological criteria. Cefpodoxime 8 to 10 mg/kg/day (administered in 2 divided doses) for 5 to 10 days was at least as effective as standard 10-day regimens of penicillin V in the treatment of children with pharyngitis and/or tonsillitis. Significant differences in favour of cefpodoxime proxetil were demonstrated in terms of clinical (1 study) and bacteriological (2 studies) criteria. The clinical efficacy of 5 days of treatment with cefpodoxime proxetil is similar to that of 10 days of treatment with penicillin V. In children with lower respiratory tract infections (primarily pneumonia), clinical and bacteriological efficacy rates achieved with cefpodoxime proxetil treatment were similar to those produced by cefuroxime axetil or amoxicillin/clavulanic acid in randomised controlled trials. Cefpodoxime proxetil also demonstrated clinical efficacy in paediatric patients with skin and soft tissue infections. In randomised studies that included both adults and children with a variety of infections (e.g. abscess, atheroma, furuncle and carbuncle, infected wounds, cellulitis), cefpodoxime proxetil showed efficacy similar to that of cefuroxime axetil or cefaclor. Cefpodoxime proxetil is well tolerated by paediatric patients, with adverse events (primarily gastrointestinal tract disturbances and skin rashes) that are consistent with those reported for other oral cephalosporins. CONCLUSION: Cefpodoxime proxetil is a third generation cephalosporin with a broad spectrum of antibacterial activity and a favourable pharmacokinetic profile which allows twice-daily administration. It is generally well tolerated and demonstrates good bacteriological and clinical efficacy in paediatric patients with various infectious diseases, including acute otitis media, tonsillitis and/or pharyngitis. Based on these characteristics, cefpodoxime proxetil is a suitable option for the treatment of paediatric patients with various common bacterial infections.     

Pharmacokinetic and tolerance studies of cefpodoxime after single- and multiple-dose oral administration of cefpodoxime proxetil.

Cefpodoxime proxetil, a third generation, broad-spectrum, oral cephalosporin, was administered in single doses of 100, 200, 400, 600, and 800 mg (dose expressed as cefpodoxime equivalents) and multiple doses of 100, 200, and 400 mg twice daily to healthy volunteers. The pharmacokinetics of the active metabolite, cefpodoxime, and tolerance of cefpodoxime proxetil were determined. Results from the single-dose study indicate that cefpodoxime exhibits nonlinear pharmacokinetics over the dose range of 100 to 800 mg. This nonlinearity is primarily due to differences in dose-normalized AUC and Cmax, urinary recovery, and half-life between one or more of the higher-dose treatment groups and the 100-mg dosing group. After multiple-dose (twice daily) administration for 15 days, steady state is achieved on the second day of dosing, and there is no drug accumulation. Cefpodoxime pharmacokinetics are linear with dose over the clinically relevant dosing range of 100 to 400 mg. Microbiologic and HPLC plasma assay results are highly correlated, with close agreement between HPLC- and microbiologic-determined pharmacokinetic parameter estimates. Cefpodoxime proxetil was well tolerated in both studies. The most frequent medical events were related to gastrointestinal problems and consisted of transient loose stools in three subjects in the single-dose study and antibiotic-associated diarrhea in one subject in the multiple-dose study.     

盐酸头孢卡品匹酯片治疗急性细菌性感染多中心双盲随机对照临床研究

目的评价头孢卡品匹酯片(第3代头孢菌素类抗生素)治疗急性细菌性感染的临床疗效和安全性。方法用多中心双盲双模拟随机平行对照试验设计,选择急性呼吸系统和泌尿系统细菌感染患者,试验组口服头孢卡品匹酯片100 mg,每日3次;对照组口服头孢泊肟酯片200 mg,每日2次,疗程5～14天。结果试验组入组135例,疗效评价128例,安全性评价135例;对照组入组134例,疗效评价129例,安全性评价134例。治疗后,2组总有效率分别为97.66%,94.57%;总的细菌清除率分别为96.36%,94.06%;药物不良反应发生率,试验组为5.19%,对照组为4.48%,2组比较差异无统计学意义,未见严重不良反应。结论头孢卡品匹酯片治疗急性呼吸系统和泌尿系统细菌感染,临床疗效确切,安全性较好。     

国产头孢泊肟酯片治疗下呼吸道细菌性感染40例

目的评价国产头孢泊肟酯片治疗下呼吸道细菌性感染的有效性和安全性。方法将78例轻度及中度下呼吸道细菌性感染患者随机分为2组，治疗组40倒口服头孢泊肟酯片200mg（2次／d），对照组38例口服头孢克洛片500mg（3次／d），疗程均为7～14d。结果治疗组与对照组临床有效率分别为87.5％与81．6％，细菌清除率分别为89.2％与85.0％，两组均无明显不良反应。结论采用头孢泊肟酯片治疗下呼吸道细菌性感染安全、有效。     

头孢泊肟酯片治疗急性细菌性感染158例的多中心随机对照研究

目的 :评价国产头孢泊肟酯片治疗急性细菌性感染的有效性和安全性。方法 :采用多中心、随机对照研究方法 ,以进口头孢泊肟酯片为对照 ,2组的用量、用法及疗程均为 10 0mg ,po ,bid ,疗程 7～14d。结果 :本研究共入组 175例病人 ,可进行临床疗效评价分析的病例 15 8例 ,试验组 77例 ,对照组81例。试验组总痊愈率和有效率分别为 70 %和92 % ;对照组总痊愈率和有效率分别为 79%和94 % ,2组细菌清除率分别为 98%和 98% ,2组比较差异均无显著意义 (P >0 .0 5 )。试验组和对照组的不良反应发生率分别为 9%和 2 % ,主要表现为口干、恶心、腹部不适及转氨酶增高等。结论 :国产头孢泊肟酯片治疗急性细菌性感染临床疗效确切 ,安全性较好。     

Clinical evaluation of a new oral cephem, cefpodoxime proxetil in children

Cefpodoxime proxetil (CPDX-PR, CS-807) was evaluated for its efficacy, safety and pharmacokinetics in children. CPDX-PR was effective in 93.6% of 47 cases with respiratory tract, middle ear, skin or urinary tract infections. Twice or 3 times daily administration of 3 mg/kg each was sufficient to treat streptococcal pharyngitis and Haemophilus influenzae infections. No severe adverse reaction was encountered in 52 cases treated with CPDX-PR. The serum half-life was approximately 2.17 +/- 0.24 hours after oral administration.     

Cefpodoxime proxetil: a comprehensive review

Cefpodoxime proxetil, a relatively new broad-spectrum third-generaation cephalosporin, has very good in vitro activity against Enterobacteriaceae, Hemophilus spp. and Moraxella spp., including beta-lactamase producers and many strains resistant to other oral agents. It also has activity against Gram-positive bacteria, especially against streptococci. Cefpodoxime has no activity against enterococci. It is well tolerated and is one of the first third-generation cephalosporins to be available in oral form. While the compound has been used most widely in the treatment of respiratory and urinary tract infections, its utility has also been demonstrated in the treatment of skin structure infections, acute otitis media, pharyngitis, tonsillitis, and sexually transmitted diseases.     

第3代口服头孢菌素——头孢泊肟酯

头孢泊肟酯口服后在肠壁水解成头孢泊肟经肠道吸收。头孢泊肟有广谱而强大的抗菌作用 ,组织分布广泛 ,T1/2 较长 ,对 β内酰胺酶稳定 ,耐受性良好 ,具有治疗剂量小 ,每日给药次数少的优点。本文主要对其抗菌活性、人体药动学、临床应用作一综述。     

The bioavailability of cefpodoxime proxetil tablets relative to an oral solution

The bioavailability of cefpodoxime proxetil tablets relative to an oral solution of cefpodoxime proxetil in a sucrose/alcohol/citric acid vehicle was studied in 11 healthy volunteers in a randomized, crossover study. Fasted subjects took one cefpodoxime proxetil 100 mg tablet or 50 mL of a 2 mg mL^?1 cefpodoxime proxetil oral solution on two separate occasions. In a third study period, all subjects took a 100 mg dose of the oral solution with a high-fat meal to investigate the effect of food on cefpodoxime proxetil absorption from the oral solution. Serial blood samples were obtained over a 24h period, and urine was collected for 48h after dosing. Cefpodoxime concentrations in plasma and in urine were determined using HPLC methods. The bioavailability of cefpodoxime proxetil tablets relative to the oral solution was 82%, as determined from AUC ratios. There was no difference in the rate of cefpodoxime absorption between dosage forms. Food had no effect on the extent of drug absorption from the oral solution but did result in delayed absorption. These results suggest that complete dissolution of cefpodoxime proxetil is critical for optimal bioavailability.     

Cerebrospinal fluid pharmacokinetics of cefpodoxime proxetil in piglets

Cefpodoxime is an oral third-generation cephalosporin used for the treatment of acute upper-respiratory tract infections caused by susceptible bacteria in children. Although not indicated for the treatment of bacterial meningitis, it is used to treat other infections produced by organisms associated with meningitis and may obscure the result of cerebrospinal fluid (CSF) cultures in children who develop meningitis while receiving oral antibiotics if sufficient concentrations are achieved in the CSF. This study evaluated the disposition of cefpodoxime and penetration into CSF in piglets. Fifteen Landacre-Camborough cross piglets (10-20 days old) received cefpodoxime proxetil oral suspension (10 mg/kg). Repeated plasma and CSF samples were collected over 24 hours for quantitation of cefpodoxime by HPLC. Pharmacokinetic analysis was performed on both plasma and CSF data. The plasma concentration versus time data for cefpodoxime were best characterized using a one-compartment model with first-order absorption. The mean (+/- SD) pharmacokinetic parameters for Cmax, tmax, and AUC0-infinity were 23.3 +/- 12.9 mg/L, 3.9 +/- 1.4 h, and 237 +/- 129 mg/L.h, respectively. CSF/plasma ratios for AUC0-infinity demonstrated a mean cefpodoxime penetration of approximately 5%. CSF penetration of cefpodoxime was evident following a single oral dose of cefpodoxime proxetil suspension. Despite the small percentage of total cefpodoxime dose distributing into the CSF, the resultant concentrations approached or exceeded the MIC90 for many bacterial pathogens considered susceptible to cefpodoxime. Accordingly, clinicians should use caution in the interpretation of CSF cultures in patients who develop clinical signs and symptoms consistent with meningitis and who have been previously treated with cefpodoxime.     

Successful Clinical Experience with Twice Daily Oral Epicillin

Summary

Epicillin was administered to 1,369 patients to evaluate the efficacy of a twice-daily regimen in the treatment of respiratory tract, urinary tract, and skin and soft-tissue infections. Results of this clinical study indicate that epicillin administered orally on a twice-a-day schedule is a safe, well-tolerated and efficacious agent for the treatment of infections caused by susceptible organisms.     

HPLC法测定头孢泊肟酯分散片中有关物质的含量

目的:建立测定头孢泊肟酯分散片中有关物质含量的方法。方法:采用高效液相色谱法。色谱柱为ODS(C18)柱,流动相为水-甲醇(55:45),流速为2.0mL·min-1,检测波长为240nm,柱温为25℃,进样量为20μL。结果:头孢泊肟酯A、头孢泊肟酯B与杂质能完全分离;头孢泊肟酯A最小检测限为1.6ng,头孢泊肟酯B最小检测限为1.2ng,其有关物质含量均<4.0%。结论:该方法简便、准确,灵敏度高,专属性强,可用于头孢泊肟酯分散片有关物质含量的测定。     

Investigation of factors responsible for low oral bioavailability of cefpodoxime proxetil

Learning about the behavior of a drug in biological environment enables application of better formulation strategies to improve bioavailability of the same. Cefpodoxime proxetil (CP) is a prodrug, which is orally administered cephalosporin with only 50% absolute bioavailability. Despite previous studies, reasons responsible for low bioavailability of CP remain poorly understood. The present study tries to ascertain reasons for the low oral bioavailability of CP. The in vitro, in situ and ex vivo studies showed interesting results, where metabolism of CP into cefpodoxime acid (CA) inside the intestinal epithelial cell and preferential efflux of CA into lumen was identified as primary reason for low oral bioavailability of CP. Presence of specific carriers or transportation mechanism on the apical side membrane of enterocyte, than basal side of the same was observed.     

头孢泊肟酯片人体相对生物利用度和生物等效性

目的:考察头孢泊肟酯片受试制剂和参比制剂的人体相对生物利用度,并评价两者的生物等效性。方法:22名健康男性志愿者随机交叉单剂量口服头孢泊肟酯片受试制剂200mg和参比制剂200mg,用HPLC法测定给药后血浆样本中头孢泊肟的浓度,用DAS软件计算其药动学参数,并评价两种制剂的相对生物利用度。结果:受试制剂和参比制剂的tmax分别为(2.6±0.6)和(2.9±0.7)h,Cmax分别为(2.9±0.8)和(3.4±0.6)mg.L-1,t1/2分别为(2.4±0.6)和(2.14±0.23)h,AUC0-t分别为(16.1±4.0)和(18.2±3.6)mg.h.L-1,AUC0-∞分别为(17.0±3.9)和(19.1±3.7)mg.h.L-1。受试制剂的相对生物利用度F0-tn和F0-∞分别为(88.6±15.6)%、(89.8±14.7)%。结论:两种制剂具有生物等效性。     

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.     

Bacampicillin Hydrochloride: Chemistry,Pharmacology, and Clinical Use

Bacampicillin hydrochloride is an orally administered ester of ampicillin that is rapidly and completely hydrolyzed in vivo to ampicillin. The most notable advantage of bacampicillin over ampicillin is its superior bioavailability — bacampicillin achieves significantly higher blood and tissue levels and attains peak blood levels more rapidly than equimolar doses of oral ampicillin. In addition, the percentage of an oral dose of ampicillin that is absorbed decreases sharply as the size of the dose is increased from 500 mg to 2 g; this phenomenon is not observed with equipotent doses of bacampicillin. The enhanced absorption of bacampicillin in the upper gastrointestinal tract results in a frequency of diarrhea that appears to be markedly lower than that of ampicillin and similar to that observed with amoxicillin. Apart from the sizable differences between bacampicillin and ampicillin with regard to oral absorption, the pharmacokinetic and pharmacologic profiles of these two agents are essentially identical. Twice daily dosing (pulse dosing) with bacampicillin has been shown in numerous clinical trials to be of equivalent efficacy to ampicillin given four times daily or amoxicillin given three times daily in the treatment of infections of the upper respiratory tract, lower respiratory tract, skin and soft tissues, and urinary tract. The unanswered question is whether twice daily ampicillin or amoxicillin would yield similar results.     

Clinical studies of cefpodoxime proxetil in respiratory tract infections

Twelve patients with respiratory tract infections were treated with cefpodoxime proxetil (CS-807, CPDX-PR), a new cephem antibiotic. It was given orally at a dose of 200 mg 2 times a day for 4 approximately 15 days. Its clinical effects were evaluated as excellent in 1 case, good in 9 cases and poor in 2 cases. The efficacy rate was 83.3%. Its bacteriological effects were evaluated as eradication in 5 strains and decrement in 1 strain. The eradication rate was 83.3%. No adverse reactions and disorder of laboratory findings due to CPDX-PR were observed.     

Lomefloxacin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic use.

The antibacterial efficacy of oral lomefloxacin has been investigated in a wide variety of infections, including respiratory and uncomplicated and complicated urinary tract infections, obstetric, gynaecological, joint, skin, oral, ear, nose, throat and eye infections. It has also been used as an otic solution in patients with otitis media and as an ophthalmic solution in the treatment of eye infections. In clinical trials its efficacy is equivalent to that of other quinolones and it is at least as effective as other antibacterial drugs ordinarily used in these infections. Lomefloxacin offers certain advantages compared with other quinolone antibacterial drugs in that it may be conveniently administered once daily and theophylline dosage adjustment does not appear to be necessary in patients receiving this bronchodilator concomitantly. Thus, orally administered lomefloxacin should prove a useful broad spectrum antibacterial drug for a wide variety of clinical infections.     

Characterization of impurities in cefpodoxime proxetil using LC–MSn

Reversed-phase liquid chromatography coupled with electrospray ionization tandem mass spectrometry (ESI-MS/MS) was used to characterize impurities in cefpodoxime proxetil, an ester-modified prodrug. Based on the mechanisms by which cephalosporins are degraded, stress tests were designed and performed. The bulk material and capsule were eluted through a C18 column with formic acid–methanol–water as the mobile phase. In total, 15 impurities were characterized in commercial samples, including 7 known impurities and 8 new impurities. The structures of these unknown compounds were deduced via comparison with the fragmentation patterns of cefpodoxime proxetil. Data from this systematic study will help improve the safety and quality of cefpodoxime proxetil.Key words: Cefpodoxime proxetil, Cephalosporins, Impurities, LC–MS, Structure identification