Cephalosporins as key lead generation beta-lactam antibiotics.

Antibiotics are antibacterial compounds that interfere with bacterial growth, without harming the infected eukaryotic host. Among the clinical agents, beta-lactams play a major role in treating infected humans and animals. However, the ever-increasing antibiotic resistance crisis is forcing the pharmaceutical industry to search for new antibacterial drugs to combat a range of current and potential multi-resistant bacterial pathogens. In this review, we provide an overview of the development, innovation, and current status of therapeutic applications for beta-lactams with a focus on semi-synthetic cephalosporins. Cephalosporin C (CPC), which is a natural secondary metabolite from the filamentous fungus Acremonium chrysogenum, plays a major and demanding role in both producing modern antibiotics and developing new ones. CPC serves as a core compound for producing semi-synthetic cephalosporins that can control infections with different resistance mechanisms. We therefore summarize our latest knowledge about the CPC biosynthetic pathway and its regulation in the fungal host. Finally, we describe how CPC serves as a key lead generation source for the in vitro and better, in vivo synthesis of 7-aminocephalosporanic acid (7-ACA), the major core compound for the pharmaceutical synthesis of current and future semi-synthetic cephalosporins. KEY POINTS: • Latest literature on cephalosporin generations • Biotechnical production of cephalosporins • In vivo production of 7-ACA.

Role of Enzymatic Activity in the Biological Cost Associated with the Production of AmpC ß-Lactamases in Pseudomonas aeruginosa.

In the current scenario of growing antibiotic resistance, understanding the interplay between resistance mechanisms and biological costs is crucial for designing therapeutic strategies. In this regard, intrinsic AmpC ß-lactamase hyperproduction is probably the most important resistance mechanism of Pseudomonas aeruginosa, proven to entail important biological burdens that attenuate virulence mostly under peptidoglycan recycling alterations. P. aeruginosa can acquire resistance to new ß-lactam-ß-lactamase inhibitor combinations (ceftazidime-avibactam and ceftolozane-tazobactam) through mutations affecting ampC and its regulatory genes, but the impact of these mutations on the associated biological cost and the role that ß-lactamase activity plays per se in contributing to the above-mentioned virulence attenuation are unknown. The same questions remain unsolved for plasmid-encoded AmpC-type ß-lactamases such as FOX enzymes, some of which also provide resistance to new ß-lactam-ß-lactamase inhibitor combinations. Here, we assessed from different perspectives the effects of changes in the active center and, thus, in the hydrolytic spectrum resistance to inhibitors of AmpC-type ß-lactamases on the fitness and virulence of P. aeruginosa, using site-directed mutagenesis; the previously described AmpC variants T96I, G183D, and ΔG229-E247; and, finally, blaFOX-4 versus blaFOX-8. Our results indicate the essential role of AmpC activity per se in causing the reported full virulence attenuation (in terms of growth, motility, cytotoxicity, and Galleria mellonella larvae killing), although the biological cost of the above-mentioned AmpC-type variants was similar to that of the wild-type enzymes. This suggests that there is not an important biological burden that may limit the selection/spread of these variants, which could progressively compromise the future effectiveness of the above-mentioned drug combinations. IMPORTANCE The growing antibiotic resistance of the top nosocomial pathogen Pseudomonas aeruginosa pushes research to explore new therapeutic strategies, for which the resistance-versus-virulence balance is a promising source of targets. While resistance often entails significant biological costs, little is known about the bases of the virulence attenuations associated with a resistance mechanism as extraordinarily relevant as ß-lactamase production. We demonstrate that besides potential energy and cell wall alterations, the enzymatic activity of the P. aeruginosa cephalosporinase AmpC is essential for causing the full attenuation associated with its hyperproduction by affecting different features related to pathogenesis, a fact exploitable from the antivirulence perspective. Less encouraging, we also show that the production of different chromosomal/plasmid-encoded AmpC derivatives conferring resistance to some of the newest antibiotic combinations causes no significantly increased biological burdens, which suggests a free way for the selection/spread of these types of variants, potentially compromising the future effectiveness of these antipseudomonal therapies.

Does the use of new cephalosporins follow the authorised, financed and approved indications? A study of their use in routine clinical practice in a tertiary hospital.

OBJECTIVES: To evaluate the appropriateness of ceftazidime-avibactam (C-A), ceftolozane-tazobactam (C-T) and ceftaroline prescriptions according to European Medicines Agency (EMA)/Spanish Agency of Medicines and Medical Devices (AEMPS) approved indications, financed indications in the Spanish health system and hospital Infection Commission (IC) recommendations in a tertiary hospital. METHODS: Observational, descriptive and retrospective study of inpatients aged ≥18 years, who were prescribed the above-mentioned antimicrobials during the period January-December 2020. Variables obtained were demographic (sex and age), pharmacological (antibiotic, use - empiric or targeted, indication) and microbiological (sensitivity testing and antibiotic tested) data. RESULTS: A total of 79 patients were included. C-A (n=40): 67.5% of patients were male, with a mean age of 61 (range 22-87) years. Empiric treatment was applied in 30% of the cases (n=12). De-escalation in 33.33% of individuals. Sensitivity testing was done in 92.86% of patients, including C-A in 57.69% of them. C-T (n=19): 89.47% of patients were male, with a mean age of 65 (range 18-82) years. An empiric approach was followed in 5.26% of subjects; de-escalation was performed in all cases due to culture with multidrug-resistant (MDR) Pseudomonas aeruginosa. Sensitivity testing was carried out in 100% of patients, including C-T in 26.32% of them. Ceftaroline (n=20): 70% of patients were male, with a mean age of 55.5 (range 23-79) years. Empiric treatment was applied to 30% of cases. In 50% of these subjects de-escalation was done. Sensitivity testing was done in 92.85% of them, but in none with ceftaroline. Regarding the percentage of appropriateness: approved EMA/AEMPS indications: C-A: 100%; C-T: 84.21%; ceftaroline: 75%; financed indications in the Spanish health system: C-A: 85%; C-T: 100%; ceftaroline: 15%; IC: C-A: 60%; C-T: 57.9%; ceftaroline: 15%. CONCLUSIONS: Our results highlight the importance of stewardship programmes in the decision-making process and in the follow-up of patients with infections caused by MDR microorganisms.

Economic comparison between ceftiofur-treated and nontreated dairy cows with metritis.

The objective was to investigate the economic effect of treating dairy cows with metritis using ceftiofur-free acid or leaving them untreated at the time of diagnosis. Cows with a fetid, watery, red-brownish vaginal discharge were diagnosed with metritis (d 0). Data from 875 dairy cows (506 primiparous and 369 multiparous) from 1 herd in northern Florida that had been part of a larger study evaluating different treatments for metritis were used for the economic analysis. Holstein cows with metritis had been randomly assigned to: Ceftiofur (CEF, n = 239) = subcutaneous injection of 6.6 mg/kg of ceftiofur crystalline-free acid in the base of the ear at d 0 and d 3; Untreated (UNT, n = 233) = no treatment applied at metritis diagnosis. Both groups could receive escape therapy if condition worsened. A group of nonmetritic healthy cows (NMET; n = 403) from the same cohort was randomly selected for comparison. Continuous outcomes such as 300-d milk production (kg/cow), milk sales ($/cow), cow sales ($/cow), treatment cost by 60 days in milk ($/cow), reproduction cost ($/cow), replacement cost ($/cow), feeding cost ($/cow), and gross profit per cow ($/cow) were analyzed using the ANOVA (MIXED procedure of SAS version 9.4). Dichotomous outcomes such as pregnancy and culling by 300 d were analyzed using logistic regression (GLIMMIX procedure of SAS). Models included the fixed effects of treatment, parity, and the interaction between treatment and parity. A stochastic analysis was performed with 10,000 iterations using the observed results from each group. The CEF treatment resulted in greater treatment cost by 60 DIM than UNT ($112 vs. $37), but resulted in a greater proportion of pregnant cows (71 vs. 61%) and decreased culling by 300 DIM (29 vs. 39%) compared with UNT. Gross profit was lesser for UNT than NMET ($2,969 vs. $3,426), and CEF was intermediate ($3,219). The stochastic analysis showed that the mean difference in gross profit between UNT and NMET was -$457; saleable milk (49%) and replacement cost (24%) accounted for most of the variation. The mean difference in gross profit between CEF and NMET group was -$207; saleable milk (82%) and initial metritis treatment cost (9%) accounted for most of the variation. The mean difference in gross profit between the UNT and the CEF group was -$250; replacement cost (41%) and cow sales (31%) accounted for most of the variation. In summary, metritis caused large economic losses when left untreated, and CEF reduced those losses by improving fertility, reducing culling and replacement cost, and reducing milk yield losses.

The effect of generic market entry on antibiotic prescriptions in the United States.

When patented, brand-name antibiotics lose market exclusivity, generics typically enter the market at lower prices, which may increase consumption of the drug. To examine the effect of generic market entry on antibiotic consumption in the United States, we conducted an interrupted time series analysis of the change in the number of prescriptions per month for antibiotics for which at least one generic entered the US market between 2000 and 2012. Data were acquired from the IQVIA Xponent database. Thirteen antibiotics were analyzed. Here, we show that one year after generic entry, the number of prescriptions increased for five antibiotics (5 to 406%)-aztreonam, cefpodoxime, ciprofloxacin, levofloxacin, ofloxacin-and decreased for one drug: cefdinir. These changes were sustained two years after. Cefprozil, cefuroxime axetil and clarithromycin had significant increases in trend, but no significant level changes. No consistent pattern for antibiotic use following generic entry in the United States was observed.

The first national survey of antimicrobial use among dentists in Japan from 2015 to 2017 based on the national database of health insurance claims and specific health checkups of Japan.

PURPOSE: To counter the global health threat of antimicrobial resistance, effective antimicrobial stewardship programs are needed to improve antimicrobial use (AMU) among dentists in addition to physicians. This study aimed to investigate the nationwide epidemiology of AMU among Japanese dentists to facilitate the development of dentist-centered programs. METHODS: We conducted a retrospective population-based study using the National Database of Health Insurance Claims and Specific Health Checkups of Japan to analyze the AMU among Japanese dentists between 2015 and 2017. AMU was quantified as the defined daily doses per 1,000 inhabitants per day (DID). The trends in dentist-prescribed AMU were examined according to antimicrobial category and administration route. We also compared outpatient oral AMU between dentists and physicians as well as between on-site and off-site dispensing. RESULTS: The DID values of dentist-prescribed AMU were 1.23 in 2015, 1.22 in 2016, and 1.21 in 2017. During this study period, outpatient oral antimicrobials comprised the majority (approximately 99%) of dentist-prescribed AMU, and cephalosporins were the most frequently prescribed antimicrobials (>60% of all antimicrobials). The DID values of outpatient oral AMU were 1.21 for dentists and 12.11 for physicians. The DID value for on-site dispensing was 0.89 in 2017, in which cephalosporins were the predominantly used antimicrobials (DID: 0.60). CONCLUSIONS: Interventions that target dentists in Japan should focus on on-site dispensing of oral antimicrobials (especially cephalosporins) for outpatients. Further studies are needed to ascertain the underlying factors of oral cephalosporin prescriptions to guide the development of effective antimicrobial stewardship programs.

Non-prescription sale of antibiotics and service quality in community pharmacies in Guangzhou, China: A simulated client method.

OBJECTIVE: To measure the situation of the non-prescription sale of antibiotics and the service quality of community pharmacies in Guangzhou, China. METHODS: A simulated client method was conducted to estimate the non-prescription sale of antibiotics and service quality based on scenarios about adult acute upper respiratory tract infection in 2019. A total of 595 community pharmacies from 11 districts were investigated in Guangzhou, China. We used binary logistic regression to evaluate the factors associated with the non-prescription sale of antibiotics. RESULTS: The proportion of non-prescription dispensing of antibiotics was 63.1% in Guangzhou, China, with a higher incidence of antibiotic dispensing without prescription in outer districts (69.3%). Cephalosporin (44.1%) and Amoxicillin (39.0%) were sold more often than other antibiotics. Chain pharmacies had better performance on the prescription sale of antibiotics and service quality. Traditional Chinese medicine was commonly recommended by pharmacy staff. CONCLUSION: Since the non-prescription sale of antibiotics is prevalent in Guangzhou, effective solutions should be determined. Strengthened public awareness and regulatory system innovation are needed.

Cultural Drivers of Antibiotic Consumption in High-Income Countries: A Global Ecological Analysis.

Background: Previous studies evaluating the cultural and structural factors underpinning the large variations in the consumption of antibiotics in high-income countries have reached different conclusions. Some studies have found that corruption plays a dominant role, whereas other studies have concluded that cultural factors such as the degree of uncertainty avoidance (UA) and performance-orientation versus cooperation-orientation (POCO) are more important. These studies have been limited to Europe, and we, therefore, aimed to expand this analysis to all high-income countries with available data. Methods: Using antibiotic consumption data from the IQVIA MIDAS database, linear regression models were constructed with country-level cephalosporin, fluoroquinolone, and macrolide consumption (defined daily doses/1,000 population/year) as the outcome variables and country-specific scores of UA and POCO (obtained from the Hofstede Index), gross domestic product/capita, world region and markers of effective governance (Control of Corruption and Regulatory Quality extracted from the World Bank data) as the explanatory variables. All data, excluding the Hofstede Indices, used country-level averages for the years 2013 to 2015. Results: Complete data were available for 37 countries from 4 world regions. Consumption of cephalosporins, macrolides, and fluoroquinolones was associated with POCO and UA, but not the markers of effective governance. In the case of macrolide consumption, the association with UA narrowly missed statistical significance. Repeat analyses limited to first European countries and second to non-European countries revealed similar findings. Conclusions: More thought should be given to construct antibiotic stewardship campaigns that are tailored to the local extent of UA and POCO.

Antimicrobial prescription patterns in a tertiary-care pediatric unit in Thailand.

BACKGROUND: Antimicrobial resistance is one of the greatest public health threats worldwide. The improper prescription of antibiotics is one factor that promotes antibiotic resistance. Access to antimicrobial surveillance data is essential when assessing the pattern and appropriateness of antimicrobial prescriptions in hospitals and for the establishment of an antimicrobial stewardship program. This study aimed to describe the rate of antimicrobial use and the pattern of prescriptions in a tertiary care pediatric unit in Thailand. METHODS: A point prevalence survey on antimicrobial use was conducted monthly between January and June 2016, using standardized tools. The survey included all inpatient pediatric beds and identified all children receiving antimicrobial treatment on the day of the survey. RESULTS: The study included 644 children, 43.3% of whom received antimicrobial treatment during hospitalization. In general wards, the rate of antimicrobial prescriptions was 37.2%; in oncology wards it was 47.0%; in intensive care units it was 38.7%, and in surgical wards it was 67.7%. Meropenem was the most prescribed antimicrobial in the general wards (24.5%) and intensive care units (28.6%), whereas antipseudomonas was the most commonly prescribed antimicrobial in the oncology ward (26.6%). For the surgical ward, the most prescribed antimicrobial was third-generation cephalosporin for both prophylaxis and treatment (39.0%). The most common reason for antimicrobial use was the treatment of infections. CONCLUSIONS: Nearly half of hospitalized children received at least one antimicrobial. This was comparable with other pediatric tertiary care centers, although the high use of meropenem was different. This study provides important baseline information on antimicrobial use in a large tertiary-care pediatric unit and could lead to a nationwide survey in the future.

Healthcare associated Clostridioides difficile infection in adult surgical and medical patients hospitalized in tertiary hospital in Belgrade, Serbia: a seven years prospective cohort study.

Introduction: Clostridioides difficile (C. difficile) infection (CDI) is one of the most common healthcare-associated (HA) infections in contemporary medicine. The risk factors (RFs) for HA CDI in medical and surgical patients are poorly investigated in countries with a limited resource healthcare system. Therefore, the aim of the study was to investigate differences in patients' characteristics, factors related to healthcare and outcomes associated with HA CDI in surgical and medical patients in tertiary healthcare centre in Serbia.Materials and Methods: A prospective cohort study was conducted including adult patients diagnosed with initial episode of HA CDI, first recurrence of disease, readmission to hospital, while deaths within 30 days of CDI diagnosis and in-hospital mortality were also recorded. Patients hospitalized for any non-surgical illness, who developed initial HA CDI were assigned to medical group, whereas those who developed initial HA CDI after surgical procedures were in surgical group. The data on patients' characteristics and factors related to healthcare were collected, too.Results: During 7-year period, from 553 patients undergoing in-hospital treatment and diagnosed with CDI, 268 (48.5%) and 285 (51.5%) were surgical and medical patients, respectively. Age ≥ 65 years, use of proton pump inhibitors, chemotherapy and fluoroquinolones were positively associated with being in medical group, whereas admission to intensive care unit and use of second- and third-generation cephalosporins were positively associated with being in surgical group.Conclusions: Based on obtained results, including significant differences in 30-day mortality and in-hospital mortality, it can be concluded that medical patient were more endangered with HA CDI than surgical ones.

Assessment of Antiviral combination therapy with Cephalosporin antibiotic for prevention of severe Influenza-A (H1N1)pdm09 infection associated secondary bacterial infection and other complications.

Secondary bacterial infection is considered as a major complication associated with severe Influenza-A (H1N1)pdm09 infection responsible for the mortalities and morbidities worldwide. Use of antibiotics in viral Influenza infection is still debatable. All the confirmed diagnosed hospitalized Influenza-A (H1N1)pdm09 infection patients fulfilling inclusion/exclusion criteria during the study period were divided into two groups based on drug therapy for initial 72 hours. Group-1 included those patients who received oral oseltamivir alone while Group-2 included patients who were initiated on oseltamivir in combination with empiric cephalosporin antibiotic within 6-8 hours after hospitalization. The patients of both groups were assessed for incidences of various complication associated with Influenza-A (H1N1)pdm09 infection. A total of 227 and 116 patients were enrolled for Group-1 and Group-2 respectively. The incidences of secondary bacterial infections were significantly less (P<0.05). Moreover, length of stay in hospitalization, need of ICU admission, multiple organ failure and need of respiratory support were also significantly less (P<0.05) for Group-2 patients. Majority of patients that suffered complications were unvaccinated and aged more than 50 years with multiple comorbidities. Among cephalosporins, cefuroxime was found to be least effective in prevention of Influenza associated complications. Early initiation of empiric antibiotic therapy in combination with oseltamivir can prevent complications associated with Influenza-A (H1N1)pdm09 infection especially in elderly and unvaccinated high risk patients. Different combinations of antibiotics and antiviral medications need to be analysed for the prevention of severe Influenza infection complications.

Relationship between drug formulary and frequently used cephalosporins, macrolides and quinolones in Japanese hospitals.

In Japan, hospitals' pharmaceutical affairs committees freely select the drugs to be purchased depending on the regulations of each hospital. This system poses a risk of the absence of essential drugs or an excess of similar drugs, and may promote inappropriate use of third-generation cephalosporins (3GCs) and quinolones. Against this backdrop, we researched availability of antibacterial agents in Japanese hospitals. We conducted a questionnaire-based study in eastern Shizuoka Prefecture, Japan. Questionnaires were sent to 33 hospitals that had established an interactive regional partnership on infection control. We analyzed the number of available oral cephalosporins, macrolides, and quinolones in each hospital, and the correlation between the number of total available antibacterial agents and the hospital scale and cephalexin availability. Thirty-one hospitals participated in this study. First-generation cephalosporin (1 GC) was available in only 22.5% of them. In all participating hospitals, 3GCs were available, with more than one 3 GC available in 74.2%. Quinolones were available in all hospitals, and more than one quinolone in 67.7%. The numbers of hospital beds and total available antibacterial agents were positively correlated and hospitals that owned cephalexin available also significantly more often owned other available antibacterial agents. 1 GC were available in only a few hospitals, while multiple 3GCs and quinolones were available in most. This situation may lead to excess use of 3GCs or quinolones in Japan. A low number of available drugs was associated with cephalexin unavailability. Outpatient antimicrobial stewardship may focus not only on the quality of medicine, but also on the prescribing environment.

Indications and classes of outpatient antibiotic prescriptions in Japan: A descriptive study using the national database of electronic health insurance claims, 2012-2015.

OBJECTIVES: To evaluate condition-specific antibiotic prescription rates and the appropriateness of antibiotic use in outpatient settings in Japan. METHODS: Using Japan's national administrative claims database, all outpatient visits with infectious disease diagnoses were linked to reimbursed oral antibiotic prescriptions. Prescription rates stratified by age, sex, prefecture, and antibiotic category were determined for each infectious disease diagnosis. The proportions of any antibiotic prescription to all infectious disease visits and the proportions of first-line antibiotic prescriptions to all antibiotic prescriptions were calculated for each infectious disease diagnosis. RESULTS: Of the 659 million infectious disease visits between April 2012 and March 2015, antibiotics were prescribed in 266 million visits (704 prescriptions per 1000 population per year). Third-generation cephalosporins, macrolides, and quinolones accounted for 85.9% of all antibiotic prescriptions. Fifty-six percent of antibiotic prescriptions were directed toward infections for which antibiotics are generally not indicated. The diagnoses with frequent antibiotic prescription were bronchitis (184 prescriptions per 1000 population per year), viral upper respiratory infections (166), pharyngitis (104), sinusitis (52), and gastrointestinal infection (41), for which 58.3%, 40.6%, 58.9%, 53.9%, and 26.1% of visits antibiotics were prescribed, respectively. First-line antibiotics were rarely prescribed for pharyngitis (8.8%) and sinusitis (9.8%). More antibiotics were prescribed for children aged 0-9 years, adult women, and patients living in western Japan. CONCLUSIONS: Antibiotic prescription rates are high in Japan. Acute respiratory or gastrointestinal infections, which received the majority of the antibiotics generally not indicated, should be the main targets of antimicrobial stewardship intervention.

Economic analysis of ceftaroline fosamil for treating community-acquired pneumonia in Spain.

Background: Adults admitted to hospital with community-acquired pneumonia (CAP) impose significant burden upon limited hospital resources. To achieve early response and possibly early discharge, thus reducing hospital expenditure, the choice of initial antibiotic therapy is pivotal.Methods: A cost-consequences model was developed to evaluate ceftaroline fosamil (CFT) as an alternative to other antibiotic therapies (ceftriaxone, co-amoxiclav, moxifloxacin, levofloxacin) for the empiric treatment of hospitalized adults with moderate/severe CAP (PORT score III-IV) from the perspective of the Spanish National Health System (NHS).Findings: Compared with ceftriaxone, the model predicted an increase in the number of CFT-treated patients discharged early (PDE) (30.6% vs. 26.1%) while decreasing initial antibiotic failures (3.8% vs. 7.6%). For patients with pneumococcal pneumonia, CFT was cost-saving vs. ceftriaxone (by 1.2%) and significantly increased PDE (32.1% vs. 24.6%). CFT resulted in cost-saving vs. levofloxacin, due lower initial antibiotic therapy costs and increased PDE (30.6% vs. 14.9%). Moxifloxacin and co-amoxiclav early response rate of 53.63% and 54.24% resulted in cost neutrality vs. CFT, with direct comparison hampered by the significantly different early response criteria utilized in the literature.Conclusions: Despite a higher unit cost, CFT is a reasonable alternative to other agents for adults hospitalized with moderate/severe CAP, given the projected higher PDE achieved with similar or lower total costs.

Decreasing and stabilising trends of antimicrobial consumption and resistance in Escherichia coli and Klebsiella pneumoniae in segmented regression analysis, European Union/European Economic Area, 2001 to 2018.

Investments to reduce the spread of antimicrobial resistance (AMR) in the European Union have been made, including efforts to strengthen prudent antimicrobial use. Using segmented regression, we report decreasing and stabilising trends in data reported to the European Surveillance of Antimicrobial Consumption Network and stabilising trends in data reported to the European Antimicrobial Resistance Surveillance Network. Our results could be an early indication of the effect of prioritising AMR on the public health agenda.

Cost-effectiveness of selective digestive decontamination (SDD) versus selective oropharyngeal decontamination (SOD) in intensive care units with low levels of antimicrobial resistance: an individual patient data meta-analysis.

OBJECTIVE: To determine the cost-effectiveness of selective digestive decontamination (SDD) as compared to selective oropharyngeal decontamination (SOD) in intensive care units (ICUs) with low levels of antimicrobial resistance. DESIGN: Post-hoc analysis of a previously performed individual patient data meta-analysis of two cluster-randomised cross-over trials. SETTING: 24 ICUs in the Netherlands. PARTICIPANTS: 12 952 ICU patients who were treated with ≥1 dose of SDD (n=6720) or SOD (n=6232). INTERVENTIONS: SDD versus SOD. PRIMARY AND SECONDARY OUTCOME MEASURES: The incremental cost-effectiveness ratio (ICER; ie, costs to prevent one in-hospital death) was calculated by comparing differences in direct healthcare costs and in-hospital mortality of patients treated with SDD versus SOD. A willingness-to-pay curve was plotted to reflect the probability of cost-effectiveness of SDD for a range of different values of maximum costs per prevented in-hospital death. RESULTS: The ICER resulting from the fixed-effect meta-analysis, adjusted for clustering and differences in baseline characteristics, showed that SDD significantly reduced in-hospital mortality (adjusted absolute risk reduction 0.0195, 95% CI 0.0050 to 0.0338) with no difference in costs (adjusted cost difference €62 in favour of SDD, 95% CI -€1079 to €935). Thus, SDD yielded significantly lower in-hospital mortality and comparable costs as compared with SOD. At a willingness-to-pay value of €33 633 per one prevented in-hospital death, SDD had a probability of 90.0% to be cost-effective as compared with SOD. CONCLUSION: In Dutch ICUs, SDD has a very high probability of cost-effectiveness as compared to SOD. These data support the implementation of SDD in settings with low levels of antimicrobial resistance.

Antibiotic stewardship based on education: minor impact on knowledge, perception and attitude.

Purpose: The purpose of this study was to implement an education-based antibiotic stewardship programme at two regional hospitals in Denmark, and thereby reduce consumption of antibiotics in general and cephalosporins and fluoroquinolones in particular. We aimed to improve physicians' knowledge, prescribing practices and perceptions and attitudes towards antibiotics, and to achieve changes in behaviour. Methods: The antibiotic stewardship programme comprised education, guidelines, audits and feedback and ward rounds by a clinical microbiologist. The ward rounds were implemented only at one hospital. The effects of the programme were evaluated using a questionnaire, audits of prescriptions (initial choice of antibiotics, indication for antibiotic treatment, re-assessment of treatment) and data on antibiotic consumption. Results: The survey revealed an improvement in junior doctors' knowledge, perception and attitude and self-reported prescribing practice. In the audit results, a larger proportion of prescribed antibiotics was in accordance with guidelines, particularly when we evaluated re-assessment of antibiotic treatment at the hospital where ward rounds had been implemented. The increase was equivalent to risk ratio (RR) 1.13 (95% confidence interval (CI): 0.95-1.35) during the intervention and RR 1.22 (95% CI 1.01-1.48) post-intervention, compared to the pre-intervention period. Penicillins as well as total antibiotic consumption increased during the study period. Conclusion: An education-based antibiotic stewardship programme can change the attitude of junior doctors and improve prescribing practices. We observed an improvement in the re-assessments of the antibiotic treatments at the hospital where a clinical microbiologist was present at ward rounds, but our persuasive methods were insufficient to reduce antibiotic consumption.

Economic comparison of systemic antimicrobial therapies for metritis in dairy cows.

Metritis is a prevalent disease with effects on production, reproduction, and survival, thereby affecting dairy farm profitability. A component of the cost of metritis is antimicrobial therapy. Some antimicrobials result in milk withhold that adds to the cost of disease. The objectives were (1) to determine cost of metritis for 2 antimicrobial treatments using a herd budget that includes costs associated with incidence of concurrent diseases, milk production and reproduction losses, and removal from the herd and (2) to apply sensitivity analysis to determine the cost of different scenarios. Cows with metritis from a previous study assigned randomly to receive ampicillin (AMP, n = 259), an antimicrobial that requires milk withhold, or ceftiofur (CEFT, n = 269), an antimicrobial with no milk withhold, were used for the economic analysis. A group of cows with no metritis (NOMET, n = 268), matched by parity and calving day, served as the baseline for comparison. The incidence of other diseases in the first 60 d postpartum, culling and death, reproductive performance, discarded milk, milk yield, total milk sold per cow, and residual cow value were used as responses. The economic analysis considered the costs associated with therapy, reproductive management, discarded milk, estimated DM consumed, income from saleable milk, and the residual cow value at 300 d postpartum or earlier if the cow was removed from the herd. Sensitivity analyses were performed considering 3 scenarios for milk and feed prices. The incidence of diseases other than metritis (NOMET, 30.4%; AMP, 45.4%; CEFT, 34.0%) and days in the hospital (NOMET, 2.7 d; AMP, 8.6 d; CEFT, 3.5 d) were greater for cows treated with AMP than CEFT. Treatment did not affect the risk of leaving the herd (NOMET, 15.5%; AMP, 15.0%; CEFT, 19.1%). The 21-d pregnancy rate was lower for cows with metritis but did not differ between AMP and CEFT (NOMET, 24.9%; AMP, 18.9%; CEFT, 17.0%). Milk yield was greater for cows without metritis than those with metritis and greater for AMP than CEFT (NOMET, 33.7 kg/d; AMP, 32.5 kg/d; CEFT, 31.2 kg/d). Cost of metritis did not differ with choice of therapy, but it increased as milk price increased. When both milk and feed prices were the average values considered ($0.44/kg and $0.26/kg, respectively), the costs of a case of metritis for AMP and CEFT were, respectively, $344 and $410 when milk was discarded and $267 and $406 when milk was fed to calves. Cost of therapy for AMP and CEFT represented 16.6 and 24.6% of the total cost of metritis when milk was discarded and 21.5 and 24.8% of the total cost of metritis when milk was fed to calves. The largest component of cost of metritis for both therapies was the reduced income from milk minus feed cost, ranging from 40.0 to 56.7%. Collectively, metritis is an expensive disease, and choice of antimicrobial therapy did not influence survival, reproduction, or cost of the disease.

Nationwide survey of indications for oral antimicrobial prescription for pediatric patients from 2013 to 2016 in Japan.

BACKGROUND: Antimicrobial resistance is a major public health concern. In 2016, the Japanese government launched a national action plan aimed at achieving a 33% and 50% reduction in the number of total and oral antimicrobial prescriptions (cephalosporins, macrolides, and quinolones) from the 2013 figures by 2020, respectively. The purpose of this study was to investigate the indications for recent antimicrobial prescriptions and to identify the primary targets for intervention to achieve the aims of the government's action plan. METHODS: Using the national health claims database, we retrospectively analyzed oral antibiotic prescriptions for Japanese children aged ≦ 15 years from 2013 to 2016. The trends were analyzed based on days of therapy (DOT) per infectious disease-related visit for each antibiotic. For patients whose chief diagnosis was an infectious disease, the number of antimicrobial prescriptions per diagnosis, their proportion, and the details of the type of antimicrobial were investigated. RESULTS: In total, 297,197,328 infectious disease-related visits were identified during 2013-2016. Total antimicrobial prescriptions showed a 3.7% reduction from 1.519 DOT/visitor in 2013 to 1.463 DOT/visitor in 2016 (Ptrend < 0.001). Antimicrobials were prescribed for 31.7% and 36.9% of children with upper and lower respiratory tract infection, accounting for 54.6% and 26.2% of all antimicrobial prescriptions, respectively. Third generation cephalosporins and macrolides comprised the majority of these prescriptions. CONCLUSIONS: Antimicrobials were commonly prescribed for children with respiratory infections. Therefore, promoting appropriate antimicrobial use in this population is required to achieve the 2020 goals set by the action plan.