Studies on oxacephems, an artificial type of beta-lactam antibiotics

A pioneering work in the field of oxacephem antibiotics which had been carried out in our research laboratories is reviewed. Our research of beta-lactam antibiotics was started in 1974 with the policy to make chemical modification at the nuclei but not the side chain of the existing beta-lactam antibiotics, with an expectation to discover a new type of antibiotics. After the success in establishing an efficient synthetic method for 3'-norcephalosporin, we started oxacephem research in 1975. We succeeded in developing three synthetic methods starting from penicillins which efficiently served to prepare numerous oxacephem (1-oxa-1-dethia-cephalosporin) derivatives. It turned out that the oxacephem nucleus was much more distorted with an increased ring strain, resulting in reduction of the beta-lactam amide resonance to a greater extent than the cephalosporin nucleus. This physicochemical properties conferred an increased chemical reactivity on the nucleus as evidenced by an increased hydrolysis rate as compared with the corresponding 1-thia counterpart. This increased chemical reactivity coupled with the reduced hydrophobicity of the oxacephem nucleus as evidenced by the lower distribution constant in a water-octanol system, characterized unique biological properties of oxacephem derivatives. These include (1) 2-16 times increase in antibacterial activity with emphasis against gram-negative bacteria; (2) increased protecting effect in vivo parallel to the increased in vitro activity; (3) reduction of the stability to beta-lactamases leading to decreased antibacterial activity against the beta-lactamase producing strains; (4) 1.6-3.2 times increase in penetrability through the outer membrane of certain gram-negative bacteria, the increase being due to the increased hydrophilicity of the oxacephem nucleus; (5) remarkably reduced binding to human serum albumin improving the efficacy of the oxacephems in the blood; (6) a remarkable change in the excretion pattern, i.e. recovery in the bile reduced and that in the urine increased. These biological characteristics are generally favorable for antibacterial agents against pathogenic diseases except for the reduced stability to beta-lactamases. This unfavorable property of the oxacephem nucleus was the only barrier for developing a new agent of the oxacephem nucleus. However, this problem was relatively easily solved by introduction of (1) the methoxy group at 7 alpha and (2) appropriately alpha-substituted acyl amide chain at 7 beta; the former and the latter substituent effectively stabilized the oxacephems to various kinds of penicillinases and cephalosporinases, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)     

Phospholipid bilayer permeability of beta-lactam antibiotics

Liposomes containing penicillinase or cephalosporinase were prepared from the phospholipids of Escherichia coli. After free beta-lactamase was inactivated by clavulanic acid or penicillanic acid sulfone followed by separation of inactivated enzyme and inhibitor from liposomes by gel filtration, the permeability of these liposomes to ampicillin, cefazolin and cephaloridine was estimated by measuring the hydrolysis of these antibiotics by the entrapped enzymes. The permeability parameter C (minute-1 microM lipid-1) of ampicillin, cefazolin and cephaloridine was calculated to be 2.35 X 10(-4), 0.33 X 10(-4) and 0.52 X 10(-4), respectively. The lipid bilayer permeability of these antibiotics was also measured by using the liposomes containing these antibiotics. About half of the initially entrapped ampicillin was released from the liposomes within 80 minutes, while no significant release of cefazolin and cephaloridine could be detected during the same period. These results clearly indicates that the lipid bilayer membrane is more permeable to ampicillin than cefazolin and cephaloridine, and they are consistent with the observations of Sawai et al., who showed that ampicillin was a more effective antibacterial drug than cefazolin and cephaloridine against the porin-deficient mutants.     

Broad-spectrum beta-lactam antibiotics with beta-lactamase inhibitors

Combining cefoperazone, piperacillin or ticarcillin with the beta-lactamase inhibitors sulbactam, tazobactam or clavulanic acid, respectively, results in compounds with activity against a wide range of Gram-positive and Gram-negative aerobic and anaerobic organisms, including strains producing beta-lactamases. Pharmacokinetics of the three combinations are similar. Cefoperazone/sulbactam can be given twice daily as opposed to a minimum of three-times-daily dosing required with the other combinations. All 9 combinations have a good safety profile, and may be administered parenterally for the treatment of severe infections in hospitalized patients, including intra-abdominal, gynaecological, skin and soft tissue infections. Additional cover may be provided by administering one of these combinations with an aminoglycoside.     

Selective spectrophotometric determination of phenolic beta-lactam antibiotics

Two simple and selective spectrophotometric methods were developed for the quantitative determination of cefoperazone sodium, cefadroxil monohydrate, cefprozil anhydrous and amoxicillin trihydrate in pure forms as well as in their pharmaceutical formulations. The methods are based on the selective oxidation of these drugs with either Ce (IV) or Fe (III) in acid medium to give an intense yellow coloured product (lambda(max)=397 nm). The reaction conditions were studied and optimized. Beer's plots were obeyed in a general concentration range of 5-30 microg ml(-1) with correlation coefficients not less than 0.9979 for the four drugs with the two reagents. The methods are successfully applied to the analysis of pharmaceutical formulations containing amoxicillin, either alone or in combination with potassium clavulanate, flucloxacillin or dicloxacillin. They were also applied to the analysis of the other three studied drugs in vials, capsules, tablets and suspensions with good recovery; percent ranged from 99.7 (+/-0.46) to 100.32 (+/-1.05) in the Ce (IV) method and 99.6 (+/-0.50) to 100.3 (+/-1.32) in the Fe (III) method. Interferences from other antibiotics and additives products were investigated.     

β-内酰胺类抗生素的药动学/药效学研究进展

综述了β-内酰胺类抗生素的药动学/药效学(PK/PD)研究进展,主要阐述了PK/PD综合参数确立的实验证据,掌握PK/PD参数有助于抗菌药物的合理应用,提高疗效,减少不良反应.     

Therapeutic considerations in using combinations of newer beta-lactam antibiotics

The in vitro activity, pharmacokinetic interactions, and clinical efficacy of newer beta-lactam antibiotic combinations are reviewed. Combinations of beta-lactam antibiotics offer an antimicrobial spectrum similar to that of aminoglycoside-beta-lactam combinations without the renal or eighth cranial nerve toxicity of aminoglycosides. Synergistic activity with beta-lactam combinations is demonstrable in vitro against a wide variety of aerobic gram-negative bacilli, but the frequency, with which it is found is substantially less than for aminoglycoside-beta-lactam combinations. Also, in vitro antagonism can be demonstrated, particularly with combinations containing an agent capable of inducing beta lactamase. Substantial alterations in the pharmacokinetics of cefotaxime and desacetylcefotaxime have been demonstrated by the concomitant administration of mezlocillin or azlocillin. In addition, the clearance of moxalactam has been shown to be reduced by concomitant administration of piperacillin, and the clearance of oxacillin is reduced by concomitant mezlocillin therapy. Dosage reductions of these drugs may be appropriate in certain situations. Several clinical trials comparing therapy with beta-lactam combinations versus aminoglycoside-containing regimens in neutropenic patients have shown no difference in overall efficacy between the two regimens, with the possible exception of infections in persistently granulocytopenic patients and perhaps in patients with Pseudomonas aeruginosa infections. beta-lactam combinations are generally less nephrotoxic, but potentially more costly when newer compounds are included, than amino-glycoside-containing regimens. These beta-lactam combinations should be reserved for use in patients at high risk for aminoglycoside toxicity.     

Microbial kinetics of beta-lactam antibiotics against Escherichia coli

Microbial kinetics of Escherichia coli NIHJ JC-2 and E. coli B/r were investigated in the presence of beta-lactam antibiotics. To maintain a constant drug concentration during the experiment, a novel technique, using a dialysis membrane tube containing the drug solution, was successfully employed. The drug-affected generation curves of E. coli exhibited common features. After the addition of drug, an apparent lag period was noted, followed by a first-order decrease of the sensitive organisms and, 6 h later, by a regrowth of resistant organisms, depending on the antibiotic concentration used. The relationship between the apparent generation rate constant, kapp, and the antibiotic concentration was found to be nonlinear. This phenomenon is consistent with a saturable receptor site model for the drug action. A good linear free energy relationship was observed between the microbial kinetic parameter, kmax, and the alkaline degradation rate constants, kOH, of the cephalosporins studied.     

The bacterial outer-membrane permeability of beta-lactam antibiotics.

Two penicillins and 5 cephalosporins were evaluated for their ability to pass through the outer-membranes of Proteus morganii, Citrobacter freundii and Escherichia coli. Cefazolin, ceftezole and cephaloridine showed high permeability through the outer-membranes of these Gram-negative bacteria. Benzylpenicillin and cephalothin, on the contrary, showed low permeability. The outer-membrane permeability of ampicillin and cephalexin varied from species to species. C. freundii was found to have the highest barrier against both the penicillins and the cephalosporins, and E. coli appeared to have a low barrier against the cephalosporins. The hydrophobic character of the beta-lactam antibiotics, which was estimated by a reversed-phase thin-layer chromatography was closely related to the outer-membrane permeability. In general, the more hydrophilic antibiotic showed the higher outer-membrane permeability. However, cephaloridine, the most lipophilic compound among the antibiotics tested, showed good permeability.     

Pharmacokinetic prediction for intravenous beta-lactam antibiotics in pediatric patients

A method for predicting pharmacokinetics in pediatric patients for intravenous beta-lactam antibiotics is proposed. We focused on the allometric relationships of pharmacokinetic parameters with individual body weights (BW) in human including healthy adults and pediatric patients. Drug concentration data for 15 intravenous beta-lactam antibiotics were collected retrospectively from the published articles and the individual pharmacokinetic parameters were re-calculated. A mixed effect modeling (MEM) was applied for the allometric relationship for those beta-lactam antibiotics, and mean and variances of inter-drug variability for the allometric parameters and also variance for intra-drug (residual) variability were estimated. Then drug-specific allometric parameters were estimated by an empirical Bayesian method using the pharmacokinetic parameters for a drug only in healthy adults as observations, and finally the individual pharmacokinetic parameters in pediatric patients were predicted. The predictability of the method was evaluated by the leave-one-out method. We also demonstrated a method for simulating plasma concentration-time profiles in pediatric patients, and the predicted time-course curves generally coincided well with the actual plasma concentration data for the tested drugs.     

ICH Q7A; 4.40 containment of beta-lactam antibiotics: an industry perspective

The ICH Q7A guidance was finalized at the Fifth International Conference on Harmonization in San Diego, Nov. 9-11, 2000, and has been implemented in Japan since Nov. 2, 2001. However, in ICH Q7A; 4.40, Containment, there is no clear stipulation about whether a dedicated or multi-purpose facility should be employed in the production of highly sensitizing materials of different types of beta-lactam antibiotics, such as cephalosporins and cephems. This study presents the threshold levels for the induction of anaphylaxis by beta-lactam antibiotics to show that it is possible to use a multi-purpose facility for the production of several different types of beta-lactam antibiotics except for penicillins, if there are validated cleaning standards based on threshold values.     

β-内酰胺类抗生素集中配置配伍稳定性探讨

目的:探讨β-内酰胺类抗生素的配伍稳定性,为临床合理用药提供依据。方法:利用中国医院知识仓库(CHKD)检索2000~2008年间β-内酰胺类抗生素配伍稳定性相关文献进行统计分析。结果:通过对温度、pH值、微粒及溶液浓度等方面分析,较精确、直观地反映出在何种条件下输液较稳定,对临床用药具有参考价值。结论:静脉药物的集中配置从配置、运输、输注的整个环节中,对药物放置的时间和储存条件有了更高要求,因此在集中配置时更应注意其配伍稳定性,保证临床用药的安全,减少不良反应的发生。     

β-内酰胺类抗生素的不良反应分析及对策

目的探讨β-内酰胺类抗生素用药过程中存在的不良反应（ADR）,分析其原因及对策,促进临床合理、安全、有效用药。方法收集本院β-内酰胺类抗生素ADR病例报告120份,根据原始报告表及相关病历资料对ADR报告中患者性别、年龄、药品剂型、给药途径、原患疾病与ADR、引起ADR的药品种类及例数、药品剂型与ADR、给药途径与ADR、不良反应累及系统及主要临床表现等进行分类统计汇总。结果发生ADR的人群以儿童和老年人居多;原患疾病以呼吸系统疾病最多;发生ADR的β-内酰胺类抗生素以头孢曲松最多;静脉给药最容易引起ADR;同时也存在着13-内酰胺类抗生素的不合理应用现象,120例ADR患者经过停药和积极的对症治疗,治愈98例,好转22例,无死亡病例发生。结论加强β-内酰胺类抗生素的合理使用,是避免和减少药物不良反应发生的关键。