Oral Cephem Research Articles

Survey of potentially inappropriate prescriptions for common cold symptoms in Japan: A cross-sectional study.

Common cold is among the main reasons patients visit a medical facility. However, few studies have investigated whether prescriptions for common cold in Japan comply with domestic and international evidence. To determine whether prescriptions for common cold complied with domestic and international evidence. This cross-sectional study was conducted between October 22, 2020, and January 16, 2021. Patients with cold symptoms who visited the two dispensing pharmacies and met the eligibility criteria were interviewed. The pharmacists at each store and a physician classified the patients into two groups: the potentially inappropriate prescribing group and the appropriate prescribing group. Of the 150 selected patients, 14 were excluded and 136 were included in the analysis. Males accounted for 44.9% of the total study population, and the median patient age was 34 years (interquartile range [IQR], 27-42). The prevalence rates of potentially inappropriate prescriptions and appropriate prescriptions were 89.0% and 11.0%, respectively and the median drug costs were 602.0 yen (IQR, 479.7-839.2) [$5.2 (IQR, 4.2-7.3)] and 406.7 yen (IQR, 194.5-537.2) [$3.5 (IQR, 1.7-4.7)], respectively. The most common potentially inappropriate prescriptions were the prescription of oral cephem antibacterial agents to patients who did not have symptoms of bacterial infections (50.4%) and β2 stimulants to those who did not have respiratory symptoms due to underlying disease or history (33.9%). Approximately 90% of prescriptions for common cold symptoms in the area were potentially inappropriate. Our findings could contribute to the monitoring of the use of medicines for the treatment of common cold symptoms.

Cephem Antibiotics: Wise Use Today Preserves Cure for Tomorrow

1. Sarah Parker, MD*,† 2. Michelle Mitchell, MD* 3. Jason Child, PharmD†‡ 1. *Division of Pediatric Infectious Diseases, University of Colorado School of Medicine/Children’s Hospital Colorado, Aurora, CO. 2. †Antimicrobial Stewardship Program, Children’s Hospital Colorado, Aurora, CO. 3. ‡Department of Pharmacy, Children’s Hospital Colorado, Aurora, CO. * Abbreviations: CAP: : community-acquired pneumonia CLSI: : Clinical Laboratory Standards Institute CSF: : cerebrospinal fluid FDA: : Food and Drug Administration GAS: : group A streptococcus IM: : intramuscular IV: : intravenous MIC: : mean inhibitory concentration MRSA: : methicillin-resistant Staphylococcus aureus MSSA: : methicillin-susceptible Staphylococcus aureus PBP: : penicillin-binding protein PD: : pharmacodynamic PK: : pharmacokinetic PRSP: : penicillin-resistant Streptococcus pneumoniae UTI: : urinary tract infection In the spirit of last month’s issue emphasizing “Doing Less” and using evidenced-based guidelines for treating pneumonia and sinusitis, we present the following feature on the judicious use of cephalosporins. Joseph A. Zenel, MD Editor-in-Chief Although cephem antibiotics are important in a pediatrician’s armamentarium, they are overused to the detriment of patients, hospitals, and communities, despite the availability of sound alternatives. Going back to the basics on mechanisms of action, resistance, and pharmacokinetic and pharmacodynamic principles facilitates smarter use and preserves cures for tomorrow. After reading this article, readers should be able to: 1. Describe in a general manner the mechanism of action, resistance, and pharmacokinetic and pharmacodynamic principles of cephem antibiotics. 2. Describe the advantages and disadvantages of oral cephem antibiotics compared with amoxicillin and amoxicillin–clavulanic acid. 3. Describe appropriate clinical situations in which to use cephem antibiotics. 4. Describe appropriate clinical situations where cephems are commonly used but could reasonably be replaced with an alternative, non-cephem antimicrobial. The cephem antibiotics were first deployed in the 1960s but did not expand into broad use until the 1970s with the development of useful semisynthetic derivatives. The cephem class includes the cephalosporins and the cephamycins, of which more than 22 antibiotics are now in clinical use (Table 1). There is no doubt that the cephem antibiotics are important weapons in a practitioner’s armamentarium; they are the most widely prescribed and largest selling class of antibiotics, with $8.5 billion spent yearly worldwide. (1) View this table: Table 1. Compiled Cephem and Comparative Penicillin Agent Pharmacokinetic and Pharmacodynamic Data That said, cephems are also arguably the most inappropriately used antibiotics in pediatrics. Approximately 40% of pediatric antibiotic use is inappropriate. This …

Laboratory and clinical studies on S-1108 in the pediatric field

Laboratory and Clinical Studies on S-1108, a new oral cephem antibiotic, were carried out to evaluate its usefulness at a dose between 2 and 4 mg/kg a day for 7 to 14 days in the pediatric field. 1) Pharmacokinetic studies S-1108 at a dose of 2 mg/kg was administered to evaluate the pharmacokinetic parameters in 1 subject. Cmax, T1/2 and AUC were 0.69 hour, 1.42 hours and 2.15 micrograms.hr/ml, respectively. 2) Antimicrobial activities MICs against various clinically isolated organisms (Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Branhamella catarrhalis, Escherichia coli and Haemophilus influenzae) were determined. The MIC values of S-1006 were similar to those of cefteram, the MICs against S. pyogenes, and H. influenzae were < or = 0.025 and 0.10 microgram/ml, respectively. 3) Clinical studies S-1108 was administered to patients with various pediatrics infections in 34 cases (upper respiratory tract infections: 12 cases, lower respiratory tract infections: 5 cases, urinary tract infections: 9 cases, skin and soft tissue infection: 6 cases, otitis media: 2 cases). Clinical efficacy rate was evaluated according to "Standard of clinical evaluation in pediatrics field". The responses were all good or excellent. 4) Side reactions There were no serious adverse reactions in any cases. The above results suggest that S-1108 is potent effective and safe agent in the pediatric field at a dose between 2-4 mg/kg (t.i.d.) a day.

各種臨床分離株の経口セフェム系薬に対する薬剤感受性とPharmacokinetics/Pharmacodynamics (PK/PD) 理論を用いたその有効性について

We compared the antimicrobial activity of commercially available oral cephem agents, cefaclor (CCL), cefroxadine (CXD), cefdinir (CFDN), cefixime (CFIX), cefpodoxime (CPDX), cefteram (CFTM), cefcapene (CFPN), and cefditoren (CDTR), against Streptococcus pneumoniae, Haemophilus influenzae, Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, Streptococcus agalactiae, Streptococcus pyogenes, and ESBL-producing bacteria isolated from clinical materials in Kansai Medical University Hospital between 2002 and 2003. Based on the Pharmacokinetics/Pharmacodynamics (PK/PD) theory, we determined the concentration of each agent at which the time above MIC (TAM) value was 40% or more, and calculated the rate of efficacy against each type of bacteria. In S. pneumoniae strains, the MIC(50,80,90) values of CDTR were 0.25, 0.5, and 0.5 microg/ml, respectively, lower than those of the other agents, demonstrating the most potent antimicrobial activity. However, the efficacy rate for CDTR calculated based on the PK/PD theory was 58.5%. CFTM showed the highest efficacy rate (66.1%). In H. influenzae strains, the antimicrobial activity of CDTR was most potent, followed by that of CFTM and that of CFPN/CFIX. The MIC90 value of CDTR was lowest (0.25 microg/ml), followed by that of CFTM (0.5 microg/ml). The efficacy rate for CDTR was 100%. This result supports that CDTR frequently eradicates H. influenzae. In E. coli strains, the MIC90 values of the above agents, excluding CCL and CXD, ranged from 0.5 to 1 microg/ml. The antimicrobial activity of CFIX against K. pneumoniae was most potent, followed by that of CFDN/CPDX and that of CFTM. In ESBL-producing bacteria, most agents showed an MIC90 value of more than 4 microg/ml. In S. agalactiae and S. pyogenes strains, all of the agents showed satisfactory MIC values. In methi- cillin-sensitive Staphylococcus aureus (MSSA) strains, CFDN and CXD showed a high efficacy rate, whereas the efficacy rates for the other agents were low. The frequent use of oral agents has increased the number of cephem-resistant bacteria. ESBL-producing bacteria become highly resistant, and the presence or absence of response can be readily evaluated. However, when a mutation of penicillin-binding protein (PBP) occurs, drug resistance is less marked. Therefore, it is difficult to evaluate the treatment response in many cases. In S. pneumoniae strains, the efficacy rates for all of the agents were low in the evaluation using the PK/PD theory, suggesting that a dose higher than the standard dose should be established. Thus, in the future, the efficacy should be evaluated based on the PK/PD theory, appropriate antimicrobial treatment should be administered, and the administration method that does not increase the number of resistant bacteria must be established.

Possible Cefcapene Pivoxil- or Clarithromycin-Induced Severe Hyperglycemia in a Patient With Type 2 Diabetes: A Case Report

There are various reasons for the deterioration of glycemic control observed in patients with diabetes, one of which is drug-induced hyperglycemia. Antibiotics, especially the fluoroquinolones, have been reported to be associated with glucose disturbances. However, induction of hyperglycemia by cephem or macrolide antibiotics has rarely, if ever, been reported. Here, we report the case of possible antibiotics-induced severe hyperglycemia in a patient with type 2 diabetes. A 67-year-old Japanese diabetic man, who was not using oral hypoglycemic agents or insulin but whose condition was controlled with diet and exercise, presented at an otolaryngology clinic with nasal discharge and rhinorrhea. His glycosylated hemoglobin (HbA1c) level had been stable at 6.6-7.2% for several years. He was diagnosed with acute sinusitis and given an oral cephem antibiotic, cefcapene pivoxil, for 1 week. His otolaryngeal symptoms were slight and disappeared soon. Thereafter, therapy was switched to a macrolide antibiotic, clarithromycin, for 3 weeks. Twenty-five days after the initiation of antibiotic therapy, severe hyperglycemia was pointed out; his random serum glucose and HbA1c levels were 29.4 mmol/L and 10.6%, respectively. The patient required insulin and oral hypoglycemic agent therapy. The Naranjo probability scale suggests that the relationship between the administration of cefcapene pivoxil or clarithromycin and the patient’s severe hyperglycemia might be possible. To the best of our knowledge, there has been no previous report of a deterioration in glycemic control in a patient with diabetes administered a cephem (cefcapene pivoxil) or macrolide (clarithromycin) antibiotic. Considering the global prescription of cephem and macrolide antibiotics, awareness of the fact that some patients are at high risk for impaired glucose tolerance is important when prescribing antibiotics. Further studies are warranted to determine the incidence rate of hyperglycemia among patients with diabetes who are administered cephem and macrolide antibiotics. J Med Cases. 2013;4(6):416-419 doi: https://doi.org/10.4021/jmc1274w

新規エステル型経口セフェム剤, S-1108の微生物学的定量法による体液内濃度測定法の検討

新規エステル型経口セフェム剤, S-1108の微生物学的定量法による体液内濃度測定法の検討

新規エステル型経口セフェム剤, S-1108: β-lactamaseに対する安定性とペニシリン結合蛋白質への親和性

新規エステル型経口セフェム剤, S-1108: β-lactamaseに対する安定性とペニシリン結合蛋白質への親和性

経口セフェム系抗菌薬S-1090のラット大腿部Staphylococcus aureus感染モデルに対する治療効果

経口セフェム系抗菌薬S-1090のラット大腿部Staphylococcus aureus感染モデルに対する治療効果

新規エステル型経口セフェム剤, S-1108の第I相臨床試験

新規エステル型経口セフェム剤, S-1108の第I相臨床試験

Update of cefditoren activity tested against community-acquired pathogens associated with infections of the respiratory tract and skin and skin structures, including recent pharmacodynamic considerations

Antimicrobial resistance rates have noticeably increased among commonly isolated species associated with respiratory tract infections and skin and skin structure infections, particularly Streptococcus pneumoniae and Staphylococcus aureus. Cefditoren, an oral 3rd-generation–like cephalosporin, has been shown to be very active against many Gram-positive and Gram-negative species with favorable attributes including bactericidal activity and stability against many β-lactamase enzymes. Clinical trial data worldwide support the use of cefditoren for infections and species that have been approved by the US Food and Drug Administration (US-FDA). This review and a contemporary study report provide an update of clinical trial and in vitro data for cefditoren especially against pathogens within the spectrum of activity since 2002. A large collection of 7279 clinical isolates collected during 2002 and 2003 from medical centers in North and Latin America and Europe were tested to confirm cefditoren potency and spectrum compared with other oral cephalosporins and other class agents. Isolates were tested at a reference laboratory using reference broth microdilution methods. Cefditoren was shown to be active against nearly all (>99%) isolates of penicillin-susceptible S. pneumoniae isolates (MIC 90, ≤0.03 μg/mL) and was the most potent orally administered cephalosporin against this organism. Cefditoren was the most active oral cephem tested against Haemophilus influenzae (MIC 90, ≤0.03 μg/mL) and had >99% activity versus both β-lactamase–positive and β-lactamase–negative isolates. The potency of cefditoren (MIC 90, 0.5 μg/mL) was similar to that of amoxicillin/clavulanate and cefdinir (MIC 90, 0.25 μg/mL) when tested against Moraxella catarrhalis. Cefditoren was the most potent cephalosporin tested against oxacillin-susceptible S. aureus with an MIC 90 value of only 1 μg/mL, and it was 100% active against the tested β-hemolytic streptococci. Using the data generated from the large collection of isolates tested in this global surveillance collection, as well as other summarized supporting studies and clinical trial information, we show that cefditoren has sustained in vitro activity and documented clinical efficacy for indications that have been approved by regulators (US-FDA).

Children's toxicology from bench to bed - Liver Injury (1): Drug-induced metabolic disturbance - Toxicity of 5-FU for pyrimidine metabolic disorders and pivalic acid for carnitine metabolism -

Congenital disorders of metabolism show a wide spectrum of symptoms as a consequence of impairment of a certain metabolic pathway by mutated enzymes resulting in abnormal accumulation of enzyme substrates, deficiency of expected products, and abnormal burden to collateral metabolic pathways, etc. However, in some occasions, depending on which pathway up to what degree of disturbance, it can be asymptomatic until a certain kind of burden is placed on to the patient. Enzyme deficiency involved in pyrimidine degradation, such as Dihydropyrimidine dehydrogenase (DPD) and Dihydropyrimidinase (DHP), has been reported with convulsion or autism as symptoms, but many asymptomatic cases are also reported. However, when the patients are treated with 5-fluorouracil, a pyrimidine analogue anticancer drug, lethal side-effects can be seen even in asymptomatic patients. Some oral cephem antibiotics have pivalic acid side chain to increase absorption rate at intestine. These antibiotics degrade into active antibiotics and pivalic acid at the intestinal wall. This pivalic acid is carnitine-conjugated and excreted into urine. Carnitine acts as a carrier of long chain fatty acid to mitochondria and to beta-oxidation, thus an important molecule for energy production by beta-oxidation and maintenance of mitochondrial function. Because of this, long term administration of such antibiotics could induce depletion of carnitine from the body and lead to low ketotic hypoglycemia, convulsion and consciousness disturbance. This paper reports some possible serious side effects closely linked to drug metabolism.

In vitro Activities of Oral Cephem and Telithromycin Against Clinical Isolates of Major Respiratory Pathogens in Japan

The in vitro antibacterial activities of oral cephem antibiotics and ketolide telithromycin against major respiratory pathogens possessing β-lactam-resistant mutations (within the pbp gene) and/or macrolide-resistant genes (erm and mef) were examined in clinical isolates collected at 66 institutes in all over the Japan between 2002 and 2003. Telithromycin showed the strongest antibacterial activity against methicillin-susceptible Staphylococcus aureus strains with and without macrolide-resistant genes, such as ermA or ermC gene. All the cephem antibiotics showed potent antibacterial activity against Streptococcus pyogenes, with minimum inhibitory concentrations (MICs) of 0.015 mg/L or lower. Cefdinir had a much higher MIC90 against genotypic penicillin-resistant Streptococcus pneumoniae (gPRSP) than cefditoren and cefcapene (8 mg/L cefdinir vs. 1 mg/L cefditoren and cefcapene). The majority of gPRSP harbored either ermB or mefA, and the antibacterial activity of telithromycin against these strains was decreased however some susceptibility was still sustained. Cefditoren exerted the strongest antibacterial activity against β-lactamase-negative ampicillin-resistant Haemophilus influenzae, with an MIC90 of 0.5 mg/L. These results underline the importance of checking the susceptibility and selecting an appropriate antibiotic against target pathogens.

Cefpodoximeに対する臨床分離株の感受性推移 (2000-2003年)

For the post-marketing surveillance of cefpodoxime proxetil (CPDX-PR, Banan), MICs of oral cephem antibacterials including CPDX against clinical isolates from 15 medical institutions all over Japan are measured yearly and the incidence rates of resistance in various species are also evaluated. In the first surveillance from June 2000 to March 2001, 1,091 isolates of 22 species were tested, 993 isolates of the same 22 species were tested in the second surveillance from April 2001 to March 2002, and 1,115 isolates of the same 22 species were tested in the third surveillance from April 2002 to March 2003. No remarkable changes in the activity of CPDX were observed against most of the species in these surveillances spanning three years and in comparison with that in the studies conducted before Banan was launched. In the study, CPDX as well as other cephem antibacterials showed a gradual decrease in activity against all the strains of Streptococcus pneumoniae and Haemophilus influenzae in proportion to the increase in the incidence rates of penicillin-resistant S. pneumoniae (PRSP) and beta-lactamase-negative ampicillin-resistant H. influenzae (BLNAR). A small percentage of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, which are high-resistant strains, were isolated. The findings of this surveillance indicate that it is necessary to pay careful attention to the trends of resistant bacteria such as PRSP, BLNAR, and ESBL-producing strains.

Cephems: fifty years of continuous research.

Since 1964, seven waves of parenteral cephems have been reported. All of them were designed to meet medical needs. The first (group I) and the third (group III) waves were very successful and drugs belonging to group III are widely used in the treatment of severe infections. A new series of compounds (group VII), with a new compound underdevelopment was designed for the treatment of Staphylococcus aureus strain resistant to methicillin but also to glyco- and lipoglycopeptides. By modifying the substituent at position 3 and 7 of the cephems rings optimal moieties have been fixed leading to potent anti-Gram-positive drugs. Alterations of substituents are still in progress to obtain optimal anti-Gram-positive (anti-MRSA) compounds. The first oral cephem cephalexin was introduced in clinical practice in 1967. Since this time, many esterified and non-esterified cephems have been synthesized and introduced in clinics. There are two groups of compounds, alpha-amino and non-alpha-amino cephems which are classified in six groups according to their chemical structure. The absorption route was explored and three transporting systems have been described according to the physico-chemical properties of these compounds, in addition prodrugs are passively absorbed.

小児急性中耳炎に対するセフゾンの効果

Cefzon® (cefdinir, CFDN, Fujisawa Pharmaceutical Co., Ltd.) is an oral cephem antibiotic which was marketed in 1991. It has been confirmed that the clinical efficacy of cefdinir in the treatment of respiratory tract infections was 85.0% or more and the safety of cefdinir was high in the field of pediatrics. In this study the clinical efficacy of cefdinir in cases of acute otitis media was investigated in 47 pediatric patients aged 3 months to 11 years and 9 months. The clinical efficacy rate was 83.0% and the bacteriological eradication rate was 79.2% in all of these patients. The main pathogens isolated from these patients were Haemophilus influenzae (41.1%), Streptococcus pneumoniae (30.4%) and coagulase negative staphylococci (CNS) (12.5%). The eradication rates of thesepathogens were 82.6% (19/23 patients) for H. influenzae and 78.6% (11/14 patients) for S. pneumoniae. The efficacy rate of cefdinir in monomicrobial infections was 89.7% (26/29 patients) but the efficacy rate in polymicrobial infections was 64.3% (9/14 patients).As adverse reactions, diarrhea was observed in 3 patients (6%) but disappeared in 1 patient 3 days after discontinuation of the drug and administration was continued in the remaining 2 patients.The superior efficacy of cefdinir in treatment of acute otitis media was attributed to the high concentrations of cefdinir which exceeded MICs against H. influenzae or S. pneumoniae in tympanic mucosa.

In Vitro Antibacterial Activity of a New Oral Cephalosporin, S-1090

A new oral cephem antibiotic S-1090 was evaluated for its in vitro antibacterial activity in comparison with cefdinir, cefpodoxime, and cefaclor. S-1090 had fairly potent antibacterial activity when compared with cefdinir, cefpodoxime, and cefaclor. At concentrations below 0.78 μg/mL, S-1090 inhibited 90% of the strains of methicillin-susceptibleStaphylococcus aureus, most streptococci,Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Proteus mirabilis, Neisseria gonorrhoeae, andHaemophilus influenzae. S-1090 was minimally active against methicillin-resistantS. aureus, enterococci,Serratia marcescens, Citrobacter freundii, Enterobacter aerogenes, andEnterobacter cloacae, and inactive againstPseudomonas aeruginosa and Xanthomonas maltophilia. S-1090 was stable to hydrolysis by various penicillinases and cephalosporinases, but was rapidly hydrolyzed by penicillinase produced byMoraxella (Branhamella) catarrhalis, by plasmid-mediated OXA-1 type penicillinase, and by cephalosporinases produced byProteus vulgaris andBacteroides fragilis. S-1090 had high affinities for the “lethal target PBPs” ofS. aureus andE. coli, and showed potent bactericidal activity against these bacterial species.

The synergic effects of quinolones and oral cephem antibiotics on Serratia marcescens.

The in-vitro effects of new quinolones and oral cephem antibiotics in various combinations on 26 strains of clinically isolated Serratia marcescens were assessed. The in-vitro activities of ofloxacin and ciprofloxacin in combination with either cefpodoxime or cefcamate were evaluated by the chequerboard titration method. These combinations showed synergistic and additive effects against most of the S. marcescens tested but no antagonism was observed. Time-kill experiments performed with two representative isolates of S. marcescens showed synergic effects with respect to the kill rates, when concentrations of quinolones and beta-lactam antibiotics, exhibiting bacteriostatic effects were combined. Exposure of S. marcescens to ciprofloxacin before the addition of cefpodoxime had no influence on the combination effect. When cefpodoxime was added first, however, the bactericidal effect was reduced. The induction of beta-lactamase by cefmetazole was enhanced by the combination of ciprofloxacin and cefmetazole. These results suggest that the synergic effects observed between new quinolones and cephem antibiotics are due to the stimulation of incorporation of cephems by combination with quinolones.

ChemInform Abstract: Studies on the Stability of δ2 and δ3 Cephem Esters. Part 1. Marked Difference in Stability Between δ2 and δ3 Cephem Prodrug Esters and Application to the Preparation of Key Intermediates for Oral Cephem Synthesis.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Phase I Clinical Studies of S-1090: Safety and Pharmacokinetics

S-1090, an oral cephem antibiotic, was given to healthy male volunteers in single (10 to 400mg) and multiple (200mg, twice a day) doses. There were no abnormalities in subjective and objective signs, or physical findings, in any subjects. The intestinal and oropharyngeal bacterial flora were not significantly affected by S-1090. These results suggest that S-1090 is a safe and well-tolerated drug. Food intake increased the absorption of S-1090, but did not affect its half-life. The plasma concentration increased with increasing doses, but at a rate less than proportional to the dose, in the single-dose studies. S-1090 was eliminated with a half-life of 2 to 3 hours after oral administration under nonfasting conditions, independent of dose. Urinary recovery rate decreased with increasing doses. The maximum plasma concentration, half-life, and area under the concentration-time curve at the dose of 100mg in nonfasting conditions were 3.78μg/ml, 2.77 hours, and 25.51μg·h/mL, respectively. S-1090 may be absorbed by both unsaturable passive and saturable active transport systems. During multiple dosing, the extent of absorption decreased slightly, but steady state was achieved within several days without changes in half-life. S-1090 binds to serum protein constantly, at a very high 97%, which might cause the long half-life of this drug. The high plasma concentration and long half-life of S-1090 are favorable for clinical use.

Therape utic effects of oral cephem antibiotics on experimental otitis media caused by Streptococcus pneumoniae in guinea pigs

Therape utic effects of oral cephem antibiotics on experimental otitis media caused by <I>Streptococcus pneumoniae</I> in guinea pigs