European Surveillance of Antimicrobial Consumption (ESAC): outpatient antibiotic use in Europe

BACKGROUND: The ESAC project, granted by DG SANCO of the European Commission, is an international network of surveillance systems, aiming to collect comparable and reliable data on antibiotic use in Europe. Data on outpatient antibiotic use were collected from 34 countries using the ATC/DDD methodology. METHODS: For the period 1997-2003, data on outpatient use of systemic antibiotics aggregated at the level of the active substance were collected and expressed in DDD (WHO, version 2004) per 1000 inhabitants per day (DID). Outpatient antibiotic (ATC J01) use in 25 European countries, able to deliver valid data, was analysed. RESULTS: Total outpatient antibiotic use in 2003 varied by a factor of 3 between the country with the highest (31.4 DID in Greece) and the country with the lowest (9.8 DID in the Netherlands) use. General use patterns in individual countries as well as trends during the period 1997-2003 are described in this paper, while major antibiotic classes (penicillins, cephalosporins, macrolides/lincosamides/streptogramins and quinolones) will be analysed in detail in separate papers. CONCLUSION: The ESAC project established for the first time a credible alternative to industry sources for the collection of internationally comparable data on antibiotic use in Europe, based on cooperation between regulatory authorities, scientific societies, health insurers and professional organizations. These data provide a tool for assessing public health strategies aiming to optimize antibiotic prescribing.     

Increase and change in pattern of hospital antimicrobial use, Denmark, 1997-2001

OBJECTIVES: To analyse the changes and compare antimicrobial consumption in public hospitals in Denmark over the period 1997-2001. METHODS: Data on the number of WHO defined daily doses (DDD) were obtained from the Danish Medicines Agency. Data on the number of bed-days were obtained from the National Board of Health. We calculated antimicrobial consumption in hospitals as the number of DDD per 100 bed-days for all antibacterials for systemic use i.e. group J01 of the Anatomical Therapeutic Chemical (ATC) classification and for classes of this group. RESULTS: During 1997-2001, antimicrobial use in hospitals in Denmark significantly increased by 18%, from 38.0 to 44.8 DDD per 100 bed-days (P < 0.005). Most of this increase (55%) was attributed to an increase in consumption of commonly used classes of antimicrobials, mainly penicillins with extended spectrum (ATC group J01CA), beta-lactamase-sensitive penicillins (J01CE) and beta-lactamase-resistant penicillins (J01CF). The 'broad-spectrum' and newer antimicrobials, i.e. combinations of penicillins with beta-lactamase inhibitor (J01CR), cephalosporins (J01DA), carbapenems (J01DH) and fluoroquinolones (J01MA) contributed to 36% of the increase. Together, these amounted to 16% of total consumption in hospitals in Denmark in 1997, rising to 19% in 2001. CONCLUSIONS: Although antimicrobial consumption in public hospitals in Denmark is low compared with other countries, the steady increase and change in pattern of their use are causes of concern, deserving close monitoring and further investigations.     

European Surveillance of Antimicrobial Consumption (ESAC): outpatient quinolone use in Europe

BACKGROUND: Data on outpatient quinolone use in Europe were collected from 25 countries within the ESAC project, funded by DG SANCO of the European Commission, using the WHO ATC/DDD methodology. METHODS: For the period 1997-2003, data on outpatient use of systemic quinolones aggregated at the level of the active substance were collected and expressed in DDD (WHO, version 2004) per 1000 inhabitants per day (DID). Because a new DDD for levofloxacin was published in the ATC 2004 index (0.5 g instead of 0.25 g) all data were recalculated accordingly. Quinolone use was analysed in detail, using a classification into three generations based on their pharmacokinetic and in vitro potency profiles, which determines the area of clinical use. RESULTS: Total outpatient quinolone use in 2003 varied by a factor of 12 between the country with the highest (3.10 DID in Portugal) and lowest (0.25 DID in Denmark) quinolone use. The second-generation quinolones represented more than 50% of the quinolone use (mainly ciprofloxacin) except for Croatia, where the first-generation was used most (mainly norfloxacin). In 22 countries, the use of second and/or third-generation quinolones increased at the expense of the use of first-generation quinolones. The new so-called respiratory quinolones (levofloxacin and moxifloxacin) represented more than 10% of quinolone use in 12 countries, with extreme seasonal variation in all these countries except for one. CONCLUSION: There has been a substantial change in the use pattern of quinolones between 1997 and 2003, since the introduction of quinolones that are effective for the treatment of respiratory tract infections. These quinolones are not the first-line antibiotics for this indication and therefore quinolone use should in general still be limited and not show substantial seasonal variation.     

National trends in appropriate antibiotics use among pediatric inpatients with uncomplicated lower respiratory tract infections in Japan

BackgroundJapan was ranked as the worst country of 36 high-income countries in terms of oral antibiotic consumptions for children. Knowing the patterns and variations of antibiotic use for pediatric inpatients with uncomplicated respiratory infections is an important step to promote judicious antibiotic use.MethodsDischarge records were extracted for children aged between 3 months and 15 years with acute lower respiratory tract infections for the fiscal years 2010–2014 using a national inpatient database in Japan. We investigated the trends in antibiotic use using mixed effect regression models and ascertained variations and clustering of the practice patterns across different hospitals using unsupervised machine learning methodology.ResultsA total of 280,298 children were included in the study. Total and broad-spectrum antibiotic use, except for fluoroquinolone, showed decreasing trends from 2010 to 2014. Additionally, the proportions of patients who received no antibiotics or only penicillin increased from 17.1% to 9.9% in 2010 to 24.5% and 13.7% in 2014, respectively. Cluster analysis showed that only one-quarter of hospitals used no antibiotics for 28.8% of children and only penicillin for 53.7% of children. In the remaining clusters of hospitals, the piperacillin, 3rd generation cephalosporins, and penicillin beta-lactamase inhibitors were used for 68.5%, 68.5%, and 69.6% of the patients who received antibiotics.ConclusionsSlightly increasing trends in narrow-spectrum antibiotics were observed. However, the treatment strategy in only one-quarter of hospitals was consistent with the current recommendations. Hospital level interventions to promote and monitor antibiotic use could be helpful to improve antibiotic use for pediatric inpatients.     

TEM-103/IRT-28 beta-lactamase,a new TEM variant produced by Escherichia coli BM4511

Clinical isolate Escherichia coli BM4511 was resistant to broad-spectrum penicillins in the presence or in the absence of beta-lactamase inhibitors but remained susceptible to cephalosporins. Resistance was due to production of a new TEM-type beta-lactamase, designated TEM-103/IRT-28, characterized by the Arg(275)Leu substitution and encoded by the ca. 62-kb pIP845 conjugative plasmid of the IncI1 incompatibility group.     

Antibiotic use and resistance of Streptococcus pneumoniae in The Netherlands during the period 1994-1999

Antibiotic use in The Netherlands during the period 1994-1999 is described in relation to the resistance of routine isolates of Streptococcus pneumoniae. The average antibiotic use in the study period was 3.4 defined daily doses per 1000 persons per day (DDD/1000/day) penicillins, 0.066 DDD/1000/day beta-lactams other than penicillins, 2.3 DDD/1000/day tetracyclines and 0.71 DDD/1000/day trimethoprim and sulphonamides, without apparent rise or decline. In contrast, the use of macrolides doubled from 0.51 DDD/1000/day in 1994 to 1.0 DDD/1000/day in 1997 and stayed at 1.07 DDD/1000/day in 1998 and 1999. In 1994 the first pneumococci isolated from patients showed 0.7% resistance to penicillin (intermediate plus full resistance), 2.5% to erythromycin, 4.2% to co-trimoxazole and 4.7% to tetracycline. In 1999 first isolates showed 1.5% resistance to penicillin, 3.8% to erythromycin, 4.4% to co-trimoxazole and 6.6% to tetracycline. The modest but significant rise in the resistance to erythromycin may have been caused by the increased use of macrolides in the years 1994-1997. The rise in resistance to penicillin seemed not to be related to increased beta-lactam use.     

某院抗生素使用情况与耐药性的关系

目的了解1998-2006年该院抗生素使用和铜绿假单胞菌、鲍曼不动杆菌的耐药情况，以及它们之间的相关关系。方法采用世界卫生组织（WHO）推荐的限定日剂量（DDD）法计算各种抗生素的用药频度（DDDs）；用ViteK2系统对临床分离菌株进行鉴定，采用K-B纸片扩散法进行药敏试验，用2004版美国实验室标准化委员会（CLSI）标准对结果进行判定，用WHONET5．3软件对数据进行处理。抗生素使用与细菌耐药之间的天系用SPSS统计软件进行偏相关分析。结果铜绿假单胞菌对头孢他啶（CAZ）、亚胺培喃（IMP）而耐药率在20％左右，对其他抗生素的耐药率都超过了40％。鲍曼不动杆菌对IMP仍敏感，耐药率不到5％，对其他抗生素耐药率都超过了40％。抗生素的总DDDs2003年达到高峰；加酶抑制剂类在2003年后DDDs上升幅度很大。相关性分析，以下关系为正相关关系，并具有统计学意义：铜绿假单胞菌对IMP的耐药率与IMP的DDDs之间，以及对头孢哌酮／舒巴坦（SCF）的耐药率与SCF的DDDs之间。鲍曼不动杆菌对哌拉西林／他唑巴坦（TZP）的耐药率与TZP的DDDs、同时与加酶抑制剂类的DDDs之间；对CAZ的耐药率与CAZ的DDDs之间；对头孢吡肟FEP的耐药率与FEP的DDDs之间；以及对SCF的耐药率与加酶抑制剂类的DDDs之间。结论广谱抗生素特别是加酶抑制剂类抗生素的使用对铜绿假单胞菌、鲍曼不动杆菌耐药水平影响较大，临床上使用应慎重。     

Molecular and biochemical analysis of AST-1, a class A beta-lactamase from Nocardia asteroides sensu stricto

A beta-lactamase gene was cloned from a Nocardia asteroides sensu stricto clinical isolate. A recombinant plasmid, pAST-1, expressed the beta-lactamase AST-1 in Escherichia coli JM109. Its pI was 4.8, and its relative molecular mass was 31 kDa. E. coli JM109(pAST-1) was resistant to penicillins and narrow-spectrum cephalosporins. The beta-lactamase AST-1 had a restricted hydrolytic activity spectrum. Its activity was partially inhibited by clavulanic acid but not by sulbactam and tazobactam. AST-1 is an Ambler class A beta-lactamase sharing 65% amino acid identity with beta-lactamase FAR-1, the most closely related enzyme.     

SHV-5, a novel SHV-type beta-lactamase that hydrolyzes broad-spectrum cephalosporins and monobactams.

SHV-5 (pI 8.2), a novel broad-spectrum beta-lactamase encoded by a ca. 150-kilobase plasmid, was found in Klebsiella pneumoniae 160. SHV-5 beta-lactamase caused decreased susceptibility to most penicillins, cephalosporins, and monobactams, except imipenem and compounds which have a C6 or C7 alpha-methoxy substituent. beta-Lactamase inhibitors (clavulanic acid, sulbactam, and tazobactam) inhibited its activity and showed a synergistic effect when associated with different hydrolyzable beta-lactam compounds. Hybridization studies suggested that this enzyme may be related to, or derived from, the SHV enzyme. Increased MICs of cephamycins and temocillin associated with a decreased synergistic effect of the inhibitors on K. pneumoniae 160 might be linked to a decrease in two outer membrane proteins.     

Streptococcus pneumoniae resistance to erythromycin and penicillin in relation to macrolide and beta-lactam consumption in Spain (1979-1997)

Streptococcus pneumoniae resistance to penicillin and erythromycin in relation to beta-lactam and macrolide consumption in Spain over 19 years (1979-1997) was studied from resistance data collected by a search of the literature. Antibiotic consumption was expressed in defined daily dosage (DDD)/1000 inhabitants/day. A significant relationship (P: < 0.001) between erythromycin resistance (MIC >/= 1 mg/L) and global macrolide consumption (r = 0.942), as well as between high-level penicillin resistance (MIC >/= 2 mg/L) and global beta-lactam consumption (r = 0.948) was observed. The relationship between erythromycin resistance and macrolide consumption was due mainly to consumption of macrolides taken twice a day (adjusted r(2) = 0.886). Prevalence of high-level penicillin resistance correlated with consumption of oral cephalosporins (adjusted r(2) = 0.877); however, there appeared to be no correlation of consumption of oral or parenteral aminopenicillins, narrow-spectrum penicillins or cephalosporins with intermediate-level penicillin resistance (MIC 0. 12-1 mg/L). The prevalence of high-level penicillin and of erythromycin resistance were also strongly correlated with each other (r = 0.903, P: < 0.001). In addition to global consumption, different categories of resistance (high or intermediate), and the differential capability of antibiotics to select resistance, must be taken into account when studying antibiotic impact on bacterial populations. Although this ecological analysis is not able to demonstrate a causal relationship between antibiotic consumption and development of resistance, it suggests that overuse of certain specific antibiotics is more likely to be related to the increase in drug-resistant strains of S. pneumoniae.     

Suppression of intrinsic resistance to penicillins in Staphylococcus aureus by polidocanol, a dodecyl polyethyleneoxid ether.

With polidocanol, it was possible to reduce the MIC as well as the MBC of methicillin, oxacillin, penicillin G, and ampicillin against resistant staphylococci. The strongest effects were obtained with methicillin and oxacillin. All strains tested could be resensitized to these penicillins independent of the original resistance levels. Polidocanol was not inhibitory by itself for Staphylococcus aureus. Furthermore, it did not inhibit the activity of staphylococcal beta-lactamase. This permits the conclusion that an intrinsic resistance mechanism is affected by this substance. Its action cannot be simply explained by an improved accessibility of the penicillin targets as uptake, and binding of methicillin and penicillin G in resistant cells was not changed by polidocanol. On the other hand, the lysis induced by combinations of this substance with small amounts of a penicillin was antagonized by chloramphenicol. This suggests that autolytic enzymes are involved in the polidocanol effect and possibly in the intrinsic resistance mechanism itself. Before polidocanol can trigger lysis, the penicillin must act first in some way. As could be seen with a susceptible strain, the resulting lysis did not exceed that obtained with penicillins alone. Thus, polidocanol does not exhibit an independent lytic mechanism but obviously is able to substitute penicillins in their lytic action.     

Properties of IRT-14 (TEM-45), a newly characterized mutant of TEM-type beta-lactamases.

IRT-14 (TEM-45) is a new mutant TEM-type beta-lactamase that was isolated from clinical Escherichia coli P37 and that confers resistance to broad-spectrum penicillins with reduced sensitivity to beta-lactamase inhibitors. The MICs of amoxicillin alone and of amoxicillin combined with 2 micrograms of clavulanic acid or 2 micrograms of tazobactam per ml were 4,096, 2,048, and 1,024 micrograms/ml, respectively. The strain was susceptible to cephalosporins, aztreonam, moxalactam, and imipenem. The enzyme was purified to homogeneity, and values of the kinetic parameters Kcat, Km, and Kcat/Km were determined for different substrates. This enzyme, with a pI of 5.2, was found to have reduced affinity for broad-spectrum penicillins and cephalosporins. The values of 50% inhibitory concentrations of clavulanic acid, sulbactam, tazobactam, and brobactam are correlated with the higher KmS for substrates. The resistance of E. coli P37 to mechanism-based inactivators results from a higher level of production of the TEM-derived enzyme due to the G-to-T substitution at position 162 (G-162-->T) in the promoter region of blaTEM and from the structural modifications resulting from the Met-69-->Leu and Arg-275-->Gln substitutions that characterize IRT-14 beta-lactamase.     

Vancomycin

Vancomycin is a narrow-spectrum bactericidal antistaphylococcal antibiotic that was introduced in 1956 because of its efficacy against resistant penicillinase-producing staphylococci. It was effective for serious staphylococcal infections for which no satisfactory alternative to penicillin G was available at the time. When methicillin and the other semisynthetic penicillins and the cephalosporins were introduced, the role of vancomycin was relegated to the alternative therapy of choice when the penicillins and the cephalosporins could not be used. In the future, vancomycin may be used more frequently in (1) methicillin-resistant Staphylococcus aureus infections, (2) streptococcal endocarditis in conjunction with an aminoglycoside in patients intolerant to penicillin or ampicillin, (3) infections associated with prosthetic devices caused by organisms with multiple antibiotic resistance, and (4) antibiotic-induced enterocolitis associated with Clostridium difficile.