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Objectives: Resistance in Neisseria gonorrhoeae to all gonorrhoea therapeutic antimicrobials has emerged. Novel therapeutic antimicrobials are imperative and the first-in-class spiropyrimidinetrione zoliflodacin appears promising. Zoliflodacin could be introduced in dual antimicrobial therapies to prevent the emergence and/or spread of resistance. We investigated the in vitro activity of and selection of resistance to zoliflodacin alone and in combination with six gonorrhoea therapeutic antimicrobials against N. gonorrhoeae., Methods: The international gonococcal reference strains WHO F (WT) and WHO O, WHO V and WHO X (strains with different AMR profiles) were examined. Zoliflodacin was evaluated alone or combined with ceftriaxone, cefixime, spectinomycin, gentamicin, tetracycline, cethromycin or sitafloxacin in chequerboard assays, time-kill curve analysis and selection-of-resistance studies., Results: Zoliflodacin alone or in combination with all six antimicrobials showed rapid growth inhibition against all examined strains. The time-kill curve analysis indicated that tetracycline or cethromycin combined with zoliflodacin can significantly decrease the zoliflodacin kill rate in vitro. The frequency of selected zoliflodacin-resistance mutations was low when evaluated as a single agent and further reduced for all antimicrobial combinations. All resistant mutants contained the GyrB mutations D429N, K450T or K450N, resulting in zoliflodacin MICs of 0.5-4 mg/L., Conclusions: Zoliflodacin, alone or in combination with sexually transmitted infection therapeutic antimicrobials, rapidly kills gonococci with infrequent resistance emergence. Zoliflodacin remains promising for gonorrhoea oral monotherapy and as part of dual antimicrobial therapy with low resistance emergence potential. A Phase III trial evaluating efficacy and safety of zoliflodacin for uncomplicated gonorrhoea treatment is planned in 2019., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To control the emerging threat of antimicrobial resistance, international policy appeals for appropriate monitoring of antimicrobial usage (AMU) at supranational, species and farm level. The aim of this study was to quantify AMU in broilers at farm and flock level in nine European countries., Methods: Antimicrobial treatment data of one flock and purchased antimicrobials over one year were collected at 181 European broiler farms. Afterwards AMU was quantified using treatment incidence (TI) per 100 days based on Defined Daily Dose (DDDvet), Defined Course Dose (DCDvet) or Used Daily Dose (UDDvet) values. Total AMU at flock level was obtained by summing the TIDDDvet of all treatments in the sampled flock (TIDDDvetFl*)., Results: The median TIDDDvetFl* was 9.0 (95% CI 5.5-10.8), meaning that broilers were treated with antimicrobials during 9% of their rearing period. TIDDDvetFl* varied considerably within and between countries. However, in every country at least one untreated flock was present. Average TIDDDvetFl* at country level ranged from 3.3 to 36.7. Polymyxins, extended-spectrum aminopenicillins and fluoroquinolones were the most used antimicrobials, accounting for 26%, 26% and 18% of total AMU, respectively. Twenty-six percent of the farms started a treatment on day 1 of production, and 49% of overall AMU was administered within the first week., Conclusions: Results show that rearing broilers without AMU is feasible. However, a huge variation in AMU in terms of amount, moment of administration and antimicrobial classes was observed. This shows that there is still ground to be covered when it comes to AMU on broiler farms., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Antibiotics are commonly classified into bactericidal and bacteriostatic agents based on their antimicrobial action. We aimed to assess whether this distinction is clinically relevant., Methods: OVID MEDLINE, EMBASE, The Cochrane Central Register of Controlled Trials (CENTRAL) and relevant references and conference proceedings using the Web of Science and Scopus databases were searched for randomized controlled trials comparing bactericidal with bacteriostatic antibiotics for treatment of severe infections. Main outcome measures were clinical cure rates and overall mortality. Abstracts of studies selected in the database search were screened by one reviewer; full-text screening and data extraction were performed by three independent reviewers., Results: Thirty-three studies were included. Approximately half of patients were treated with bacteriostatic monotherapy. Infections covered were pneumonia (n=13), skin and soft tissue infections (n=8), intra-abdominal infections (n=4) and others (n=8). Neither clinical cure rates [risk ratio (RR), 0.99; 95% CI, 0.97-1.01; P=0.11] nor mortality rates (RR, 0.91; 95% CI, 0.76-1.08; P=0.28) were different between patients treated with bactericidal drugs and those treated with bacteriostatic drugs. Subgroup analyses showed a benefit for clinical cure rates associated with linezolid and increased mortality associated with tigecycline. In meta-regression, clinical cure rates remained higher in patients treated with linezolid (P=0.01); tigecycline displayed a close to significant association with increased mortality (P=0.05) if compared with other bacteriostatic agents., Conclusions: The categorization of antibiotics into bacteriostatic and bactericidal is unlikely to be relevant in clinical practice if used for abdominal infections, skin and soft tissue infections and pneumonia. Because we were not able to include studies on meningitis, endocarditis or neutropenia, no conclusion regarding these diseases can be drawn., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Data on more than a decade of outpatient use of tetracyclines, sulphonamides and trimethoprim, and other antibacterials in Europe were collected from 33 countries as part of the European Surveillance of Antimicrobial Consumption (ESAC) project, funded by the European Centre for Disease Prevention and Control (ECDC)., Methods: For the period 1997-2009, data on outpatient use of systemic tetracyclines, sulphonamides and trimethoprim, and other antibacterials aggregated at the level of the active substance were collected and expressed in defined daily doses (DDD; WHO, version 2011) per 1000 inhabitants per day (DID). Using the Anatomical Therapeutic Chemical (ATC) classification, trends in the use of tetracyclines (J01A), sulphonamides and trimethoprim (J01E) and other antibacterials (J01X) over time, seasonal variation and composition of use were analysed., Results: In 2009, the variations in outpatient use of systemic tetracyclines, sulphonamides and trimethoprim, and other antibacterials between countries, and also in the composition of use over time, were huge. For tetracyclines a significant and for sulphonamides and trimethoprim a non-significant decrease in use was observed between 1997 and 2009 in Europe. The seasonal variation in their use significantly decreased over time. For the other antibacterials, no significant changes in the volume of use or its seasonal variation were seen., Conclusions: As for all other major antibiotic subgroups, a striking variation in use and composition of use between countries in Europe was observed for outpatient use of tetracyclines, sulphonamides and trimethoprim, and other antibacterials. In combination with the decreasing use, especially of recommended substances, this represents an opportunity not only to reduce antibiotic use but also to improve its quality.

Objectives: Our objective was to develop and test standardized methods for collection and statistical analysis of longitudinal data on hospital antibacterial use from different countries., Methods: We collected data on monthly supply of antibiotics from pharmacies in one hospital from each of 18 European countries. We applied a standardized method to classify drugs, measure use in defined daily doses and compare the effect of using occupied bed-days (OBDs) or admissions as denominators for longitudinal analysis., Results: Antibiotic use increased in 14 (78%) hospitals and decreased in 4 hospitals. For 16 (89%) hospitals, adjustment of antibiotic use with OBDs resulted in larger changes over time than adjustment with admissions. Inclusion of all hospital clinical activity variables (admissions, length of stay and OBDs) in multivariate time series analysis identified distinct hospital groups. Nine (50%) hospitals had statistically significant changes in antibiotic use (six increasing and three decreasing) that were not explained (n = 3) or only partially explained (n = 6) by change in clinical activity. Three (17%) hospitals had no significant change in antibiotic use. In the remaining six hospitals, apparent changes in antibiotic use were largely explained by changes in clinical activity., Conclusions: This is the first study to use a standardized method for data collection and longitudinal analysis of antibiotic use in different hospitals. These data suggest that determination of changes in antibiotic exposure of hospital patients over a period of time is unreliable if only one clinical activity variable (such as OBDs) is used as the denominator. We recommend inclusion of admissions, OBDs and length of stay in statistical, time series analysis of antibiotic use. This model is also relevant to longitudinal analysis of infections in hospitals.

Objectives: This study examined antibiotic utilization patterns in Turkey between 2001 and 2006., Methods: A comprehensive collection and analysis of Turkish antibiotic data from 2001 to 2006 was conducted. The anatomical therapeutic chemical (ATC) classification and the defined daily dose (DDD) methodology were used to calculate antibiotic consumption. Data were presented as DDD/1000 inhabitant-days, and the relation between antimicrobial consumption and governmental reimbursement policy was evaluated., Results: Total utilization of antibiotics increased from 14.62 to 31.36 DDD/1000 inhabitant-days between 2001 and 2006. The largest increase took place after the implementation of social insurance reform (SIR) in 2005, as evidenced by the DDD ratio increasing 1.87-fold after SIR went into effect. The largest increase occurred in the prescription of penicillins, from 7.13 in 2001 to 14.09 in 2006., Conclusions: In Turkey, antibiotic consumption increased markedly in recent years, in a close relationship, to a new reimbursement policy following the implementation of the SIR, which facilitated the prescription and consumption of drugs compared with the earlier SIR conditions.

Background: In North America use of second-generation macrolides such as clarithromycin and azithromycin is popular due to favourable dosing and adverse event profiles. However, studies have also shown that use of second-generation macrolides promotes carriage of macrolide-resistant nasopharyngeal and oral streptococci. The present study was undertaken to characterize overall antibiotic use including macrolide antibiotics among children in British Columbia., Methods: Population-based data from British Columbia were analysed to determine antibiotic prescribing patterns for outpatient prescriptions from 1996 to 2003. Antibiotic prescription rates per 1000 children per year were evaluated by age (0-4, 5-9, 10-14, <15 years old), sex and physician diagnosis., Results: From 1996 to 2003, the overall BC prescription rate in children <15 years old decreased by one-third from 720 to 488 per 1000 children. The decrease in the rate of antibiotic consumption over time was seen across all age strata; however, the largest decrease (33%) was seen in children between the ages of 0-4 years. From 1996 to 2003, use of penicillins and cephalosporins decreased by 40% and 30%, respectively. This trend of decreasing antibiotic use with beta-lactams was seen in all age groups but the greatest decline was in the age group of 0-4 years (P value <0.05). During this time, macrolide use increased significantly (24%) from 102 to 126 per 1000 children (P value <0.001). This increase was seen in all age groups but again the greatest increase was seen in children of age between 0 and 4 years. Within the macrolides, use of erythromycin decreased by 72% (from 83 to 23 per 1000 children) while clarithromycin use increased by almost 3-fold (18-67 per 1000 children) and azithromycin use increased 81-fold (0.4-35 per 1000 children). In 2003, antibiotics were primarily being used for the treatment of upper respiratory tract infections, acute otitis media and bronchitis., Conclusions: Overall antibiotic use has declined in children; however, there is increased use of macrolides which may have ramifications on macrolide-resistant streptococci, including Streptococcus pneumoniae and group A streptococci. A large proportion of antibiotic use in children is for upper respiratory tract infections and bronchitis, indications where there is a high likelihood that the aetiology is viral rather than bacterial.

Objectives: The aim of this study was to establish whether there was a relationship between the number of antibacterial agents used and total antibiotic use in European hospitals., Methods: A total of 139 hospitals from 30 countries supplied data on antibiotic use (ATC group J01) for 2001, expressed as the number of defined daily doses per 100 occupied bed-days (DDD/100 BD) and also numbers of different antibiotics used., Results: Participating hospitals used a median of 46 antibiotics in 2001 (range 16-82). The most frequently used antibiotic per hospital accounted for a median of 16.5% (range 7.2-60.9%) of total use and the 10 most frequently used agents accounted for a median of 73.7% (range 53.0-98.5%) of total use. Numbers of antibiotics used varied significantly by European geographical region (Kruskal-Wallis test, P = 0.001). The median total antibiotic use was 49.6 DDD/100 BD. A statistically significant relationship was found between the number of antibiotics used and total antibiotic use (Spearman's rank, r = 0.40 and P < 0.01) for all hospitals. Individual correlations were significant in Western (r = 0.57, P < 0.01) and Southern Europe (r = 0.67, P < 0.01) only., Conclusions: The quantitative use of antibiotics in European hospitals was highly variable as was the number of different antibiotics used. In the two areas exhibiting highest total use, the greater the number of antibiotics used, the higher the total use of these drugs. Intervention studies are now needed to ascertain whether or not successful antibiotic restriction policies can reduce total antibiotic use and subsequently reduce antibiotic resistance.

Objectives: To collect reliable, comparable and publicly available data on hospital use of antibiotics in Europe aggregated at the national level (1997-2002)., Methods: Consumption data of systemic antibiotics in Anatomical Therapeutic Chemical (ATC) class J01 were collected and expressed in defined daily doses (DDD) per 1000 inhabitants per day. Valid data for 2002 were available for 15 countries, and 6 year trends for 10 countries. Comparison with ambulatory care (AC) consumption data was possible in 14 countries., Results: In 2002, median national hospital antibiotic consumption in Europe was 2.1 DDD/1000 inhabitants/day in Europe, ranging from 3.9 in Finland and France to 1.3 in Norway and Sweden. Hospital care (HC) consumption as a proportion of total antibiotic consumption ranged from 17.8% to 6.4%. The consumption of hospital-specific antibiotics ranged from 0.43 DDD/1000 inhabitants/day in Greece and 0.08 in Sweden. Six-year trends in consumption were stable, except for rising co-amoxiclav exposure and more rapid market penetration of new antibiotics (e.g. levofloxacin) in some countries. There was a strong, positive correlation between the extent of antibiotic use in AC and in HC (Spearman coefficient 0.745; P = 0.002), both for overall use and for use of five main classes (not macrolides and 'others'). In contrast to AC consumption no substantial seasonal variation in consumption was observed., Conclusions: It was cumbersome but feasible to collect ecological data on hospital antibiotic consumption in a set of 15 European countries on a retrospective basis, illustrating substantial cross-national variations in the extent and distribution of exposure to antibiotics in hospital care.

Of the interventions designed to reduce antibiotic resistance rates in hospitals, one that is currently attracting considerable interest, particularly in the intensive care unit setting, is antibiotic cycling or rotation. Cycling is the scheduled rotation of one class of antibiotics with one or more different classes exhibiting comparable spectra of activity; in order to fulfil the definition, the cycle must be repeated. Following a search of the literature we identified 11 articles in which the authors claimed to have evaluated the efficacy of this intervention. Only four were suitable for review, but, owing to multiple methodological flaws and a lack of standardization, the results of these studies do not permit reliable conclusions regarding the efficacy of cycling. Further studies are therefore required in order to resolve this question. However, before such studies can be undertaken, there are a great many issues relating to cycling which must be addressed. For the time being, we advise against the routine implementation of this measure as a means of reducing antibiotic resistance rates.

In the present battle against the rising tide of resistance, several interventions have been proposed to help control the situation. One of these is a process of planned antibiotic restriction, introduced through cycling drug selection based on local surveillance. Although such antibiotic cycling has been the subject of much discussion for 20 years, there are relatively few data available to assess its worth. A recent systematic review found only four studies worthy of inclusion and concluded that antibiotic cycling could not, at present, be promoted as a methodology to control resistance. This paper considers the complete literature and through demonstrating consistent benefits across the breadth and depth of the findings, suggests that whereas further work is required, nevertheless antibiotic cycling-as part of a suite of control measures-is a valid option.

Antibiotic use has led to increased resistance to certain group markers: penicillin, erythromycin and ciprofloxacin for beta-lactams, macrolides and quinolones, respectively. The influence of resistance to markers in decreasing susceptibility to the drugs included (on the basis of chemical structure) in the corresponding antibiotic group can be defined as 'resistance class effect'. In the case of macrolides, this effect is dependent on the prevalent resistant phenotype among the isolates of the target bacteria: the class effect exists completely if the mechanism of resistance is constitutive MLS(B) (all macrolides are affected by resistance to erythromycin), and only partially if the mechanism is the efflux M phenotype (all but 16-membered macrolides are affected). In Spain, the first case is exemplified by Streptococcus pneumoniae and the second by Streptococcus pyogenes. For beta-lactams and quinolones, resistance to the group markers results in large decreases in the antimicrobial activity of the less potent members of the group, penicillin being a better driver of resistance for oral cephalosporins than for aminopenicillins, and ciprofloxacin being a better driver for older rather than for the newer quinolones, which have enhanced anti-pneumococcal activity. Empirical prescription guidelines based on the pharmacoepidemiology of resistance, recommending the use of potent drugs that are less influenced by resistance to the marker, may help to counter the spread of resistance in the community.

The responses of hypermutable Escherichia coli strains to selection with antibiotics having different endogenous resistance potentials were determined. Selections with rifampicin or ciprofloxacin at 4 x MIC, i.e. conditions where they act as single target agents against RpoB and GyrA, respectively, demonstrated that some hypermutators generated resistant mutants with frequencies up to 1000-fold higher than normal strains. Furthermore, individual mutants recovered from hypermutable hosts often exhibited higher levels of resistance to the drugs than mutants arising in normal hosts. Exposure to ciprofloxacin at 16 x MIC, i.e. conditions where it has low endogenous resistance potential, failed to select resistant mutants in hypermutable or normal hosts (mutation frequency <10(-11)). Consistent with these findings, the highest estimated mutation frequency for selection at 16 x MIC in a hypermutable host would be 4.4 x 10(-15) (mutT), calculated by determining the individual mutation frequencies for first-step ciprofloxacin resistance and second-step resistance arising in hosts already harbouring single first-step mutations in gyrA at codons 83 or 87. The frequency with which second-step ciprofloxacin resistance mutations arose was suppressed in hypermutators and demonstrated at most a 10-fold increase in mutation rate compared with non-hypermutator hosts. Second-step mutants may contain mutations in mar, since a survey of 170 second-step ciprofloxacin-resistant mutants derived from both hypermutator and non-hypermutator parents demonstrated that they all possessed increased resistance to chloramphenicol, a phenotype associated with mar mutations. Exposure to 4 x MIC of D-cycloserine, cefotaxime or polymyxin B (agents with multiple targets or membrane activity) failed to select resistant mutants in normal or hypermutator hosts (mutation frequency <10(-11)); however, continuous culture in the presence of sub-lethal concentrations of D-cycloserine (0.25 x MIC) selected resistant mutants in hypermutators after c. 33 generations, compared with c. 44 generations in normal hosts. Since hypermutable bacteria occur naturally, our data emphasize that successful new drugs will need to possess low endogenous resistance potentials.

The high prevalence of nosocomial infections in critically ill ICU patients is associated with high antibiotic consumption. Besides its economic impact, there is the constant threat of selection and induction of antibiotic resistance. Surveillance studies recording the incidence of infections, antibiotic use, and antimicrobial susceptibilities of pathogens supply vital information regarding infection control and prevention of antibiotic resistance. In order to analyse antibiotic consumption we recorded antibiotic use in a general ICU during one year by categorizing the indications for antibiotic use into three groups; (i) prophylaxis; (ii) therapy for a bacteriologically proven infection (BPI); (iii) therapy for a non-bacteriologically proven infection (non-BPI). Bronchoscopic techniques were used to diagnose pneumonia. In practice, BPI must be treated, but a proportion of antibiotics prescribed for non-BPI may be unnecessary. The subdivision in BPI and non-BPI may help to identify these cases. In all, 515 patients were admitted to ICU and 36% of these had at least one infection. Of all infections, 53% were ICU-acquired and 99% of these occurred in intubated patients. Antibiotics were prescribed in 61% of admissions. Of all antibiotics prescribed for therapy, 49% were for respiratory tract infections, 19% for abdominal infections and 13% for sepsis eci. Categorized by indication, 59% of all antibiotic prescriptions were for BPI, 28% for non-BPI and 13% for prophylaxis. A theoretical reduction of 25% in the number of non-BPI prescriptions would result only in a 7% decrease of total antibiotic use. We conclude that almost all antibiotics prescribed were for intubated patients and for BPI. Respiratory infections were the single most common infection and accounted for 49% of all antibiotics used. Therefore, in our setting, prevention of respiratory tract infections is probably the most effective mode to reduce antibiotic use.

Application of pharmacodynamic principles for interpretation of data generated by the Alexander Project is possible for beta-lactam, quinolone and macrolide antibiotics. For beta-lactams, the time that serum concentrations remain above the MIC of the pathogen (T > MIC) is the parameter most closely linked with outcome. It has been shown that T > MIC need be only 50-60% of a dose interval. Since the MIC has the greatest influence on this parameter, a conservative estimate of activity would use the MIC90. The only beta-lactam antibiotics in the Alexander Project for which T > MIC90 for the four major pathogens (Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Staphylococcus aureus) exceeded 50% of the dose interval were amoxycillin/clavulanate (500/125 mg) and ceftriaxone. For macrolides, T > MIC is relevant for erythromycin and clarithromycin, but not azithromycin, for which AUC is the parameter most closely linked to outcome. Erythromycin, clarithromycin and azithromycin showed efficacy against M. catarrhalis only at MIC90. Quinolones (ciprofloxacin and ofloxacin), for which AUC is also the relevant pharmacodynamic parameter, had the greatest activity against H. influenzae and M. catarrhalis at MIC90, but were less effective against S. pneumoniae and S. aureus. Susceptibility data such as those provided by the Alexander Project can aid clinicians in choosing appropriate treatment for LRTI based on pharmacodynamic principles.