Do dietary interventions exert clinically important effects on the bioavailability of ß-lactam antibiotics? A systematic review with meta-analyses.

BACKGROUND: Managing drug-food interactions may help to achieve the optimal action and safety profile of ß-lactam antibiotics. METHODS: We conducted a systematic review with meta-analyses in adherence to PRISMA guidelines for 32 ß-lactams. We included 166 studies assessing the impact of food, beverages, antacids or mineral supplements on the pharmacokinetic (PK) parameters or PK/pharmacodynamic (PK/PD) indices. RESULTS: Eighteen of 25 ß-lactams for which data on food impact were available had clinically important interactions. We observed the highest negative influence of food (AUC or Cmax decreased by >40%) for ampicillin, cefaclor (immediate-release formulations), cefroxadine, cefradine, cloxacillin, oxacillin, penicillin V (liquid formulations and tablets) and sultamicillin, whereas the highest positive influence (AUC or Cmax increased by >45%) for cefditoren pivoxil, cefuroxime and tebipenem pivoxil (extended-release tablets). Significantly lower bioavailability in the presence of antacids or mineral supplements occurred for 4 of 13 analysed ß-lactams, with the highest negative impact for cefdinir (with iron salts) and moderate for cefpodoxime proxetil (with antacids). Data on beverage impact were limited to 11 antibiotics. With milk, the extent of absorption was decreased by >40% for cefalexin, cefradine, penicillin G and penicillin V, whereas it was moderately increased for cefuroxime. No significant interaction occurred with cranberry juice for two tested drugs (amoxicillin and cefaclor). CONCLUSIONS: Factors such as physicochemical features of antibiotics, drug formulation, type of intervention, and patient's health state may influence interactions. Due to the poor actuality and diverse methodology of included studies and unproportionate data availability for individual drugs, we judged the quality of evidence as low.

Insights into antibiotic cefaclor mineralization by electro-Fenton and photoelectro-Fenton processes using a Ti/Ti4O7 anode: Performance, mechanism, and toxic chlorate/perchlorate formation.

A comparative degradation of antibiotic cefaclor (CEC) between Ti/Ti4O7 and Ti/RuO2 anodes, in terms of degradation kinetics, mineralization efficiency, and formation of toxic chlorate (ClO3-) and perchlorate (ClO4-), was performed with electrochemical-oxidation (EO), electro-Fenton (EF), and photoelectro-Fenton (PEF) processes. Besides, CEC degradation by EF with boron-doped diamond (BDD) anode was also tested. Results showed CEC decays always followed pseudo-first-order kinetics, with increasing apparent rate constants in the sequence of EO < EF < PEF. The mineralization efficiency of the processes with Ti/Ti4O7 anode was higher than that of Ti/RuO2 anode, but slightly lower than that of BDD anode. Under the optimal conditions, 94.8% mineralization was obtained in Ti/Ti4O7-PEF, which was much higher than 64.4% in Ti/RuO2-PEF. The use of Ti/RuO2 gave no generation of ClO3- or ClO4-, while the use of Ti/Ti4O7 yielded a small amount of ClO3- and trace amounts of ClO4-. Conversely, the use of BDD led to the highest generation of ClO3- and ClO4-. The reaction mechanism was studied systematically by detecting the generated H2O2 and •OH. The initial N of CEC was released as NH4+ and, in smaller proportion, as NO3-. Four short-chain carboxylic acids and nine aromatic intermediates were also detected, a possible reaction sequence for CEC mineralization was finally proposed.

Cefaclor causes vagus nerve-mediated depression-like symptoms with gut dysbiosis in mice.

Antibiotics are increasingly recognized as causing neuropsychiatric side effects including depression and anxiety. Alterations in central serotonin and 5-HT receptor expression are implicated in the pathogenesis of anxiety and depression, which are highly comorbid with gastrointestinal disorders. Nevertheless, it is still unclear how antibiotics can cause anxiety and depression. In this study, oral administration of cefaclor, a second-generation cephalosporin antibiotic, induced anxiety- and depression-like behaviors and colitis with gut microbiota alteration in mice. Cefaclor reduced serotonin levels and fluctuated 5-HT receptor mRNA expressions such as Htr1a, Htr1b, and Htr6 in the hippocampus. Vagotomy attenuated the cefaclor-induced anxiety- and depression-like symptoms, while the cefaclor-induced changes in gut bacteria alteration and colitis were not affected. Fluoxetine attenuated cefaclor-induced anxiety- and depression-like behaviors. Furthermore, fluoxetine decreased cefaclor-resistant Enterobacteriaceae and Enterococcaceae. Taken together, our findings suggest that the use of antibiotics, particularly, cefaclor may cause gut dysbiosis-dependent anxiety and depression through the microbiota-gut-blood-brain and microbiota-gut-vagus nerve-brain pathway. Targeting antibiotics-resistant pathogenic bacteria may be a promising therapeutic strategy for the treatment of anxiety and depression.

Efficacy of antimicrobials or placebo compared to amoxicillin-clavulanate in children with acute otitis media: a systematic review.

BACKGROUND: Acute otitis media (AOM) is the inflammation of the middle ear. It constitutes one of the most frequent infections which affects children and usually occurs between 6 to 24 months of age. AOM can emerge due to viruses and/or bacteria. The aim of the current systematic review is to assess in children between 6 months and 12 years of age with AOM, the efficacy of any antimicrobial agent or placebo compared with amoxicillinclavulanate, to measure the resolution of AOM or symptoms. METHODS: The medical databases PubMed (MEDLINE) and Web of Science were used. Data extraction and analysis were performed by two independent reviewers. Eligibility criteria were set, and only randomised control trials (RCTs) were included. Critical appraisal of the eligible studies was performed. Pooled analysis was conducted using the Review Manager v. 5.4.1 software (RevMan). RESULTS: Twelve RCTs were totally included. Three (25.0%) RCTs studied the impact of azithromycin, two (16.7%) investigated the impact of cefdinir, two (16.7%) investigated placebo, three (25.0%) studied quinolones, one (8.3%) investigated cefaclor and one (8.3%) studied penicillin V, compared to amoxicillin-clavulanate. In five (41.7%) RCTs, amoxicillin-clavulanate proved to be superior to azithromycin, cefdinir, placebo, cefaclor and penicillin V, while in seven (58.3%) RCTs its efficacy was comparable with other antimicrobials or placebo. The rates of AOM relapse after treatment with amoxicillin-clavulanate were comparable to those of other antimicrobials or placebo. However, amoxicillin-clavulanate was more effective in eradicating Streptococcus pneumoniae from the culture, when compared to cefdinir. The results of the meta-analysis were not evaluated due to substantial heterogeneity between studies. CONCLUSIONS: Amoxicillin-clavulanate should be the treatment of choice for children between 6 months and 12 years of age with AOM.

Insertion Sequences Determine Plasmid Adaptation to New Bacterial Hosts.

Plasmids facilitate the vertical and horizontal spread of antimicrobial resistance genes between bacteria. The host range and adaptation of plasmids to new hosts determine their impact on the spread of resistance. In this work, we explore the mechanisms driving plasmid adaptation to novel hosts in experimental evolution. Using the small multicopy plasmid pB1000, usually found in Pasteurellaceae, we studied its adaptation to a host from a different bacterial family, Escherichia coli. We observed two different mechanisms of adaptation. One mechanism is single nucleotide polymorphisms (SNPs) in the origin of replication (oriV) of the plasmid, which increase the copy number in E. coli cells, elevating the stability, and resistance profile. The second mechanism consists of two insertion sequences (ISs), IS1 and IS10, which decrease the fitness cost of the plasmid by disrupting an uncharacterized gene on pB1000 that is harmful to E. coli. Both mechanisms increase the stability of pB1000 independently, but only their combination allows long-term maintenance. Crucially, we show that the mechanisms have a different impact on the host range of the plasmid. SNPs in oriV prevent the replication in the original host, resulting in a shift of the host range. In contrast, the introduction of ISs either shifts or expands the host range, depending on the IS. While IS1 leads to expansion, IS10 cannot be reintroduced into the original host. This study gives new insights into the relevance of ISs in plasmid-host adaptation to understand the success in spreading resistance. IMPORTANCE ColE1-like plasmids are small, mobilizable plasmids that can be found across at least four orders of Gammaproteobacteria and are strongly associated with antimicrobial resistance genes. Plasmid pB1000 carries the gene blaROB-1, conferring high-level resistance to penicillins and cefaclor. pB1000 has been described in various species of the family Pasteurellaceae, for example, in Haemophilus influenzae, which can cause diseases such as otitis media, meningitis, and pneumonia. To understand the resistance spread through horizontal transfer, it is essential to study the mechanisms of plasmid adaptation to novel hosts. In this work we identify that a gene from pB1000, which encodes a peptide that is toxic for E. coli, and the low plasmid copy number (PCN) of pB1000 in E. coli cells are essential targets in the described plasmid-host adaptation and therefore limit the spread of pB1000-encoded blaROB-1. Furthermore, we show how the interplay of two adaptation mechanisms leads to successful plasmid maintenance in a different bacterial family.

Quantification of cefaclor in human plasma using SIL-IS LC-ESI-MS/MS for pharmacokinetics study in healthy Chinese volunteers.

A steady, high-efficiency, and precise liquid chromatography-electrospray ionization-tandem mass spectrometry method was established and validated using cefaclor-d5 as the stable isotope-labeled internal standard for quantification of cefaclor in human plasma. One-step protein precipitation was applied to extract human plasma samples using methanol as precipitant. An Ultimate XB C18 column (2.1 × 50.0 mm, 5.0 µm) was used to achieve chromatographic separation. Mobile phases of gradient elution were an aqueous solution containing 0.1% formic acid (mobile phase A) and an acetonitrile solution containing 0.1% formic acid (mobile phase B). Electrospray ionization in positive-ion mode was applied to detect under multiple reaction monitoring mode. Target fragment ion pairs of cefaclor and stable isotope-labeled internal standard, respectively, were m/z 368.2 → 191.1 and m/z 373.2 → 196.1. Linear range of this method was between 20.0 and 10,000.0 ng/ml, with coefficient of determination (R2 ) >0.9900. Seven concentrations of quality control samples were used: 20.0 ng/ml (lower limit of quantitation), 60.0 ng/ml (low quality control), 650 ng/ml (middle quality control), 5000 ng/ml (arithmetic average middle quality control [AMQC]), 7500 ng/ml (high quality control), 10,000 ng/ml (upper limit of quantification), and 40,000 ng/ml (dilution quality control [DQC]). The method was validated for selectivity, lower limit of quantitation, linearity, accuracy, precision, recovery, matrix effect, dilution reliability, stability, carryover, and incurred sample reanalysis. This stable isotope-labeled internal standard liquid chromatography-electrospray ionization-tandem mass spectrometry approach has been successfully applied to study the pharmacokinetics of cefaclor dry suspension among healthy Chinese volunteers.

Identification of potential biomarkers and pathogenesis in neutrophil-predominant severe asthma: A comprehensive bioinformatics analysis.

BACKGROUND: Airway neutrophilia has been associated with asthma severity and asthma exacerbations. This study attempted to identify biomarkers, pathogenesis, and therapeutic molecular targets for severe asthma in neutrophils using bioinformatics analysis. METHODS: Fifteen healthy controls and 3 patients with neutrophilic severe asthma were screened from the Gene Expression Omnibus (GEO) database. Based on the analysis of differentially expressed genes (DEGs), functional and pathway enrichment analyses, gene set enrichment analysis, protein-protein interaction network construction, and analysis were performed. Moreover, small-molecule drug candidates have also been identified. RESULTS: Three hundred and three upregulated and 59 downregulated genes were identified. Gene ontology function enrichment analyses were primarily related to inflammatory response, immune response, leukocyte migration, neutrophil chemotaxis, mitogen-activated protein kinase cascade, Jun N-terminal kinase cascade, I-kappaB kinase/nuclear factor-κB, and MyD88-dependent toll-like receptor signaling pathway. Pathway enrichment analyses and gene set enrichment analysis were mainly involved in cytokine-cytokine receptor interaction, the TNF signaling pathway, leukocyte transendothelial migration, and the NOD-like receptor signaling pathway. Furthermore, 1 important module and 10 hub genes (CXCL8, TLR2, CXCL1, ICAM1, CXCR4, FPR2, SELL, PTEN, TREM1, and LEP) were identified in the protein-protein interaction network. Moreover, indoprofen, mimosine, STOCK1N-35874, trapidil, iloprost, aminoglutethimide, ajmaline, levobunolol, ethionamide, cefaclor, dimenhydrinate, and bethanechol are potential drugs for the treatment of neutrophil-predominant severe asthma. CONCLUSION: This study identified potential biomarkers, pathogenesis, and therapeutic molecular targets for neutrophil-predominant severe asthma.

Cephalosporins-induced intestinal dysbiosis exacerbated pulmonary endothelial barrier disruption in streptococcus pneumoniae-infected mice.

Antibiotic abuse is growing more severe in clinic, and even short-term antibiotic treatment can cause long-term gut dysbiosis, which may promote the development and aggravation of diseases. Cephalosporins as the broad-spectrum antibiotics are widely used for prevention and treatment of community-acquired respiratory tract infection in children. However, their potential consequences in health and disease have not been fully elaborated. In this study, the effects of cefaclor, cefdinir and cefixime on intestinal microbiota and lung injury were investigated in Streptococcus pneumoniae (Spn)-infected mice. The results showed that the proportion of coccus and bacillus in intestinal microbiota were changed after oral administration with cefaclor, cefdinir and cefixime twice for 10 days, respectively. Compared with the Spn-infected group, the proportion of Bifidobacterium and Lactobacillus in intestine were significantly reduced, while Enterococcus and Candida was increased after cephalosporin treatment. Furthermore, 3 cephalosporins could obviously increase the number of total cells, neutrophils and lymphocytes in BALF as well as the serum levels of endotoxin, IL-2, IL-1ß, IL-6 and TNF-α. Mechanically, cephalosporins accelerated Spn-induced pulmonary barrier dysfunction via mediating the mRNA expressions of endothelial barrier-related proteins (Claudin 5, Occludin, and ZO-1) and inflammation-related proteins (TLR4, p38 and NF-κB). However, all of those consequences could be partly reversed by Bifidobacterium bifidum treatment, which was closely related to the elevated acetate production, indicating the protective effects of probiotic against antibiotic-induced intestinal dysbiosis. Therefore, the present study demonstrated that oral administration with cephalosporins not only disrupted intestinal microecological homeostasis, but also increased the risk of Spn infection, resulting in severer respiratory inflammation and higher bacterial loads in mice.

Risk factors of anaphylaxis in Korea: Identifying drug-induced anaphylaxis culprits using big data.

Drug-induced anaphylaxis is a fatal medical condition whose incidence has been increasing continuously. Due to differences between genetic backgrounds and health care systems, different populations may be prone to various causative drugs. Using the Health Insurance Service and Assessment Service database, we investigated culprit drugs for drug-induced anaphylaxis and common medication risk factors in the Korean general population. We collected medical prescription histories within 3 days prior to anaphylaxis between January 2011 and December 2019 from the HIRA database. Designed as a case-crossover study, the attributable visits (case visits) were matched to medical visits (control visits) with the drug sets for each visit. We collected a list of medication risk factors for anaphylaxis and calculated the risk ratio of each agent using the chi-square test and conditional logistic regression analysis. A total of 159,473 individuals were listed in the database with a diagnosis of anaphylaxis in the HIRA from 2011 to 2019. After evaluating the suitability of control visits for matching with a case visit, 8168 subjects and 767 drugs were analyzed. The chi-square analysis identified 31 drugs as potential risk factors for drug-induced anaphylaxis in Korea. After applying a conditional logistic regression analysis for each agent, 5 drugs were found to be the common medication risk factors for drug-induced anaphylaxis: cefaclor, iopromide, iohexol, iomeprol, and tolperisone. We found 5 medication risk factors that showed the highest risk of drug-induced anaphylaxis and their degree of risk using an objective methodology in the Korean general population.

[Suppurative Thrombophlebitis of the Posterior Neck Caused by Streptococcus constellatus: A Case Report and Literature Review].

We report a rare case of suppurative thrombophlebitis of the posterior neck caused by Streptococcus constellatus. A 69-year-old female patient was admitted to the hospital with neck pain and fever, which had persisted for 16 days prior to hospitalization. On day 1 (day of admission), blood cultures (later identifying S. constellatus) were performed, and ceftriaxone (CTRX) IV (2 g SID) was started. On day 3, suppurative thrombophlebitis of the posterior neck was diagnosed by CT scan. The antimicrobials were changed from CTRX to ampicillin/sulbactam IV (12 g QID) to guard against the possibility of complicated infection with Fusobacterium spp. or Prevotella spp. On day 17, a CT scan revealed that the thrombus remained. Therefore, oral edoxaban (30 mg SID) was started. On day 27, the patient was discharged after her medication was changed to oral amoxicillin/clavulanate (1500 mg/375 mg TID). On day 33, the amoxicillin/clavulanate was changed to oral cefaclor (1500 mg TID) and edoxaban was discontinued due to itching. On day 45, the course of cefaclor was completed. The patient went on to follow an uneventful course with no relapses or complications for two years since the conclusion of treatment. These results suggest that when a patient presents with persistent neck pain accompanied by fever, suppurative thrombophlebitis of the posterior neck should be considered. In antimicrobial therapy, the treatment could be switched from intravenous to oral. In addition, direct-acting oral anticoagulants may be an alternative to other forms of anticoagulants.

Population-Based Incidence of New Ampicillin, Cephalexin, Cefaclor, and Sulfonamide Antibiotic "Allergies" in Exposed Individuals with and without Preexisting Ampicillin, Cephalexin, or Cefaclor "Allergies".

BACKGROUND: There is a theoretical concern, unconfirmed by population-based challenge data, that clinically significant, immunologically mediated hypersensitivity occurs among ß-lactams sharing side chains. OBJECTIVE: To determine the population-based allergy incidence associated with the use of ß-lactams sharing exact R1 side chains (ampicillin, cephalexin, and cefaclor [ACC]), with or without a current ACC allergy or a sulfonamide antibiotic allergy for comparison. METHODS: All courses of ACC and trimethoprim-sulfamethoxazole used by any Kaiser Permanente California members in 2017 and 2018, with follow-up through January 2019, were identified along with their preexisting antibiotic allergy status and all new antibiotic-specific allergies reported within 30 days of course initiation. RESULTS: A total of 1,167,713 courses of ACC were administered to individuals with no sulfonamide antibiotic or ACC allergy and 4,771 new ACC allergies (0.41%) were reported. Moreover, 130,032 courses of ACC were administered to individuals with a sulfonamide antibiotic allergy and no ACC allergy, and 904 new ACC allergies (0.70%) were reported. There were 5,958 courses of ACC administered to individuals with an ACC allergy, 2,341 who also had sulfonamide antibiotic allergy, and 52 new ACC allergies (0.87%) were reported. CONCLUSIONS: The incidence of new ACC allergy reports is minimally and non-specifically increased among individuals with a preexisting ACC or sulfonamide antibiotic allergy compared to the baseline incidence in the population. This argues against clinically significant, immunologically mediated cross-reactivity among ß-lactams sharing exact side chains in individuals with preexisting but unconfirmed ß-lactam allergy. Any previously reported, even unrelated antibiotic allergy appears to be a risk factor for reporting a new antibiotic allergy.

Cefaclor-induced hypersensitivity: Differences in the incidence of anaphylaxis relative to other 2nd and 3rd generation cephalosporins.

Cefaclor, a second-generation oral cephalosporin, is the most frequently prescribed cephalosporin in Korea. Studies, however, have yet to analyze the incidence of cefaclor-associated adverse drug reactions (ADRs), including hypersensitivity (HS), according to total national usage rates. This study aimed to investigate the incidence rates and clinical features of cefaclor ADRs reported to the Korean Adverse Event Reporting System (KAERS) and Health Insurance Review and Assessment Service (HIRA) database for the most recent 5 years. Reviewing the HIRA database, which contains information on all insurance claims, including prescribed medications and patient demographics, we identified the total number of individuals who had been prescribed cefaclor and other cephalosporins including 2nd generation without cefaclor and 3rd generation antibiotics from January 2014 to December 2018. Additionally, we retrospectively analyzed all ADRs reported to the KAERS for these drugs over the same study period. Incidence rates for ADRs, HS, and anaphylaxis to cefaclor were 1.92/10,000 persons, 1.17/10,000 persons, and 0.38/10,000 persons, respectively, lower than those to other 2nd and 3rd cephalosporins. Among all ADRs, HS (60.9% vs. 43.6% vs. 44.8%, P <0.001) and anaphylaxis (19.8% vs. 4.6% vs. 4.7%, P <0.001) were more common for cefaclor than for other 2nd and 3rd cephalosporins. Females, individuals under 65 years of age, concomitant use of drugs, and serious ADRs were more strongly associated with HS to cefaclor than with HS to other 2nd and 3rd cephalosporins. In a nationwide database for the Korean population, the incidence of cefaclor-induced ADRs, particularly HS and anaphylaxis, was high. Female sex, age younger than 65 years, and concomitant use of drugs may be associated with HS to cefaclor.

Cefaclor Monohydrate-Loaded Colon-Targeted Nanoparticles for Use in COVID-19 Dependent Coinfections and Intestinal Symptoms: Formulation, Characterization, Release Kinetics, and Antimicrobial Activity.

Corona virus disease-2019 (COVID-19) emerged in Wuhan, China in December 2019 and was declared as a pandemic by the World Health Organization in March 2020. Although there is no complete treatment protocol for COVID-19, studies on this topic are ongoing, and it is known that broad-spectrum antibiotics such as cephalosporins are used for coinfections and symptoms in COVID-19 patients. Studies have shown that Staphylococcus aureus and Escherichia coli bacteria can cause symptoms such as diarrhea and coinfections accompanying COVID-19. Therefore, in this study, colon-targeted cefaclor monohydrate (CEF)-loaded poly(lactic-co-glycolic acid) (PLGA)-Eudragit S100 nanoparticles (NPs) were prepared using a nanoprecipitation technique. The particle sizes of the CEF-loaded NPs were between 171.4 and 198.8 nm. The encapsulation efficiency was in the range of 58.4%-81.2%. With dissolution studies, it has been concluded that formulations prepared with Eudragit S100 (E-coded) and Eudragit S100+PLGA (EP-coded) are pH-sensitive formulations and they are targetable to the colon, whereas the formulation prepared only with PLGA (P-coded) can release a higher CEF rate in the colon owing to the slow release properties of PLGA. The release kinetics were fitted to the Korsmeyer-Peppas and Weibull models. The antibacterial activity of E-, EP-, and P-coded formulations was 16-fold, 16-fold, and 2-fold higher than CEF, respectively, for S. aureus and E. coli according to the microdilution results. As a result of the time killing experiment, all formulations prepared were found to be more effective than the antibiotic itself for long periods. Consequently, all formulations prepared in this study hope to guide researchers/clinicians in treating both gram-positive and gram-negative bacteria-induced infections, as well as COVID-19 associated coinfections and symptoms.

HPLC/ESI-MS identification of diastereomers of Impurity E - Degradation products of cefaclor.

A seven years old sample of cefaclor stored in room conditions, as a solid, has been analyzed by using high performence liquid chromatography/electrospray ionization-mass spectrometry. As a result of the sample degradation process, two diastereomers of Impurity E have been found to have formed. It is reasonable to assume that the diastereomers are formed due to the isomerization of C6 carbon atom. They have almost identical fragmentation patterns in both positive and negative ion mode. On the other hand, the diastereomers have different efficiencies of formation of dimer ions, under ESI conditions, especially in negative ion mode.

Cefaclor as a first-line treatment for acute uncomplicated cystitis: a retrospective single-center study.

BACKGROUND: Wide-spectrum antibiotics have been favored to treat acute uncomplicated cystitis (AUC) for a long time, leading to the emergence of multi-drug resistant bacteria. We hypothesize that narrow-spectrum antibiotics might mitigate the issue and aim to investigate the clinical efficacy of cefaclor in patients with AUC. METHODS: We retrospectively reviewed the clinical data of female outpatients with AUC treated with cefaclor and evaluated the safety and clinical efficacy. Clinical cure was defined as the elimination of clinical symptom under 4 white blood cells (WBCs) per high power field on microscopy. RESULTS: Overall, 223 women with AUC were enrolled. Escherichia coli was the dominant pathogen (n = 160; 68.6%), followed by Klebsiella species and E. coli-extended spectrum ß-lactamase (ESBL) (n = 19; 8.1% and n = 18; 7.7%). Overall success rate was 94.0% (n = 219) and susceptibility rate of cefazolin was 84.1%, which was close to that of levofloxacin (82.9%). Ampicillin showed the lowest rate of 63.7% with a significantly greater resistance rate of 35.3% among all antibiotics (P < 0.001). In the subgroup analysis, the success rate in patients with resistance to levofloxacin or cefazolin was 100% (n = 24) or 93.3% (n = 14). The rate in patients with resistance to both antibiotics was 60.0% (n = 9), and the pathogens in the other 40.0% (n = 6) of patients with treatment failure were E. coli-ESBL. CONCLUSION: Cefaclor showed excellent efficacy in AUC patients, even in those with in vitro resistance to cefazolin or levofloxacin. Cefaclor may be considered as a first-line option in patients with AUC and a second-line option for those with levofloxacin treatment failure.

Integrative strategy to determine residual proteins in cefaclor produced by immobilized penicillin G acylase.

There is a growing trend in the pharmaceutical industry towards substituting conventional chemical synthesis routes of semi-synthetic ß-lactam antibiotics (SSBAs) through environmentally sustainable enzymatic processes. These have advantages such as cost reduction in terms of solvent and waste treatment and time saving owing to fewer reaction steps. Penicillin G acylase (PGA) is an industrially important enzyme that is mainly used to catalyze the synthesis of SSBAs. In this study, we established an integrative strategy using three different analytical methods for determining the PGA-associated residual protein content, which is a critical quality issue in the end product. Cefaclor was taken as representative example of SSBAs. High-performance liquid chromatography coupled with fluorescence detection (HPLC-FD) allowed the routine analysis of PGA residual proteins and other low molecular weight (MW) impurities with high detection specificity and sensitivity, comparable to those of the Bradford assay and microfluidic protein chip electrophoresis. However, these latter two methods were superior for quantitative and qualitative analysis, respectively, and should be regarded as necessary adjuncts to the HPLC-FD method. By combining the three methods, trace levels of residual proteins were detected in four (out of 13) cefaclor bulk samples from two different manufacturers, with a major protein MW of ∼63 kDa. This suggests that the higher MW PGA subunit tends to persist in the end product. The integrative determination strategy described here can be used to evaluate SSBA bulk samples and monitor the process of SSBA manufacturing by enzymatic methods, especially in terms of inter-batch consistency and process stability.