Prevalence, drivers and surveillance of antibiotic resistance and antibiotic use in rural China: Interdisciplinary study.

This study aimed to characterise antibiotic prescribing and dispensing patterns in rural health facilities in China and determine the community prevalence of antibiotic resistance. We investigated patterns and drivers of antibiotic use for common respiratory and urinary tract infections (RTI/UTI) in community settings, examined relationships between presenting symptoms, clinical diagnosis and microbiological results in rural outpatient clinics, and assessed potential for using patient records to monitor antibiotic use. This interdisciplinary mixed methods study included: (i) Observations and exit interviews in eight village clinics and township health centres and 15 retail pharmacies; (ii) Urine, throat swab and sputum samples from patients to identify potential pathogens and test susceptibility; (iii) 103 semi-structured interviews with doctors, patients, pharmacy workers and antibiotic-purchasing customers; (iv) Assessment of completeness and accuracy of electronic patient records through comparison with observational data. 87.9% of 1123 recruited clinic patients were prescribed antibiotics (of which 35.5% contained antibiotic combinations and >40% were for intravenous administration), most of whom had RTIs. Antibiotic prescribing for RTIs was not associated with presence of bacterial pathogens but was correlated with longer duration of infection (OR = 3.33) and presence of sore throat (OR = 1.64). Fever strongly predicted prescription of intravenous antibiotics (OR = 2.87). Resistance rates in bacterial pathogens isolated were low compared with national data. 25.8% of patients reported antibiotics use prior to their clinic visit, but only 56.2% of clinic patients and 53% of pharmacy customers could confirm their prescription or purchase included antibiotics. Diagnostic uncertainty, financial incentives, understanding of antibiotics as anti-inflammatory and limited doctor-patient communication were identified as key drivers of antibiotic use. Completion and accuracy of electronic patient records were highly variable. Prevalence of antibiotic resistance in this rural population is relatively low despite high levels of antibiotic prescribing and self-medication. More systematic use of e-records and in-service training could improve antibiotic surveillance and stewardship in rural facilities. Combining qualitative and observational anthropological methods and concepts with microbiological and epidemiological investigation of antibiotic resistance at both research design and analytic synthesis stages substantially increases the validity of research findings and their utility in informing future intervention development.

The pharmacodynamics of minocycline alone and in combination with rifampicin against Staphylococcus aureus studied in an in vitro pharmacokinetic model of infection.

BACKGROUND: Tetracyclines are widely used as oral therapy of MRSA infection, however, the pharmacodynamic underpinning is absent. OBJECTIVES: We employed an in vitro pharmacokinetic model to study the pharmacodynamics of minocycline alone and in combination with rifampicin. METHODS: An exposure-ranging design was used to establish fAUC/MIC targets for static, -1 log drop and -2 log drop effects against Staphylococcus aureus for minocycline and in combination with rifampicin. We then simulated 7-10 day human dosing of minocycline and the combination. RESULTS: The minocycline fAUC/MIC for 24 h static effect and -1 log drop in bacterial load were 12.5 ±â€Š7.1 and 23.3 ±â€Š12.4. fAUC/MIC targets for static and -1 log drop were greater at 48 and 72 h. The addition of simulated free rifampicin associated with dosing 300 mg q12h reduced the 24 h minocycline fAUC/MICs. Simulations performed over 7-10 days exposure indicated that for minocycline standard human doses there was a 1-3 log reduction in viable count and no changes in population profiles. Addition of rifampicin resulted in larger reductions in staphylococcal load but emergence of resistance to rifampicin. There was no resistance to minocycline. CONCLUSIONS: An fAUC/MIC minocycline target of 12-36 is appropriate for S. aureus. Addition of rifampicin decreases bacterial load but results in emergence of resistance to rifampicin. Unusually, there was no emergence of resistance to minocycline.

In vitro pharmacodynamics of omadacycline against Escherichia coli and Acinetobacter baumannii.

BACKGROUND: The pharmacodynamics of omadacycline have been extensively studied against Gram-positive pathogens but less information is available for Gram-negative pathogens. We describe the pre-clinical pharmacodynamics of omadacycline against Escherichia coli and Acinetobacter baumannii. METHODS: An in vitro dilutional pharmacokinetic model was used. Exposure experiments with fAUC/MIC ratios ranging from 0 to 1200 were performed using five strains of E. coli and five strains of A. baumannii. Reduction in bacterial load and changes in population profiles were measured. RESULTS: The fAUC/MIC targets against E. coli for 24 h static and -1 log reduction in load were 25.3 ±â€Š17.2 and 42.7 ±â€Š32.5, respectively. For A. baumannii the fAUC/MIC for 24 h static effect was 108.1 ±â€Š38.6. Changes in population profiles were observed for E. coli at fAUC/MIC ratios of ≤200 and for A. baumannii up to 1200. MICs were increased 2-32 fold. CONCLUSIONS: fAUC/MIC targets for A. baumannii are greater than for E.coli and changes in population profiles more likely. E. coli fAUC/MIC targets align with in vivo data and will be useful in determining omadacycline dosing for this pathogen.

Daptomycin in the treatment of enterococcal bloodstream infections and endocarditis: a EUCAST position paper.

SCOPE: This position paper describes the view adopted by EUCAST on the role of daptomycin in the treatment of serious infections caused by Enterococcus species. BACKGROUND: High-dose daptomycin is considered effective in the treatment of enterococcal bloodstream infection (BSI) and endocarditis, although published clinical experience with the latter condition is limited. METHODS: EUCAST reviewed the available published data on pharmacokinetics-pharmacodynamics (PK-PD), resistance selection, clinical efficacy and safety for the use of 10-12 mg/kg/day of daptomycin for these conditions, noting that the doses licensed by the European Medicines Agency are only 4-6 mg/kg/day, and only for infections caused by Staphylococcus aureus. FINDINGS AND RECOMMENDATIONS: The PK-PD evidence shows that, even with doses of 10-12 mg/kg/day, it is not possible to treat infections caused by isolates at the upper end of the wild-type distributions of Enterococcus faecalis (with MICs of 4 mg/L) and E. faecium (with MICs of 4 or 8 mg/L). For this reason, and because there are ongoing issues with the reliability of laboratory testing, EUCAST lists daptomycin breakpoints for Enterococcus species as "IE"-insufficient evidence. EUCAST advises increased vigilance in the use of high-dose of daptomycin to treat enterococcal BSI and endocarditis. Additional PK-PD studies and prospective efficacy and safety studies of serious Enterococcal infections treated with high-dose daptomycin may permit the setting of breakpoints in the future.

Impact of rapid microbial identification on clinical outcomes in bloodstream infection: the RAPIDO randomized trial.

OBJECTIVES: Bloodstream infection has a high mortality rate. It is not clear whether laboratory-based rapid identification of the organisms involved would improve outcome. METHODS: The RAPIDO trial was an open parallel-group multicentre randomized controlled trial. We tested all positive blood cultures from hospitalized adults by conventional methods of microbial identification and those from patients randomized (1:1) to rapid diagnosis in addition to matrix-assisted desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) performed directly on positive blood cultures. The only primary outcome was 28-day mortality. Clinical advice on patient management was provided to members of both groups by infection specialists. RESULTS: First positive blood culture samples from 8628 patients were randomized, 4312 into rapid diagnosis and 4136 into conventional diagnosis. After prespecified postrandomization exclusions, 2740 in the rapid diagnosis arm and 2810 in the conventional arm were included in the mortality analysis. There was no significant difference in 28-day survival (81.5% 2233/2740 rapid vs. 82.3% 2313/2810 conventional; hazard ratio 1.05, 95% confidence interval 0.93-1.19, p 0.42). Microbial identification was quicker in the rapid diagnosis group (median (interquartile range) 38.5 (26.7-50.3) hours after blood sampling vs. 50.3 (47.1-72.9) hours after blood sampling, p < 0.01), but times to effective antimicrobial therapy were no shorter (respectively median (interquartile range) 24 (2-78) hours vs. 13 (2-69) hours). There were no significant differences in 7-day mortality or total antibiotic consumption; times to resolution of fever, discharge from hospital or de-escalation of broad-spectrum therapy or 28-day Clostridioides difficile incidence. CONCLUSIONS: Rapid identification of bloodstream pathogens by MALDI-TOF MS in this trial did not reduce patient mortality despite delivering laboratory data to clinicians sooner.

An in vitro biofilm model of Staphylococcus aureus infection of bone.

Chronic osteomyelitis is difficult to treat, with biofilm growth and the diffusion barrier to antibiotics presented by bone contributory factors. The aim of this study was to develop and evaluate an in vitro model of osteomyelitis. A bioluminescent strain of Staphylococcus aureus was grown in bone blocks made from bovine femur. Light output was insufficient for detection of bacterial cells within bone by 24 h and viable counting of crushed bone blocks was used to determine bacterial survival. Challenge of 72 h biofilms with gentamicin and daptomycin for 24 h demonstrated that only concentrations of 10 times the clinical peak serum target levels (100 mg l-1 gentamicin and 1000 mg l-1 daptomycin) resulted in significant reductions in cell viability compared to controls. Once daily dosing over 7 days resulted in ≥3 log reductions in cell numbers by 48 h. Thereafter no significant reduction was achieved, although emergence of resistance was suppressed. Determination of antibiotic concentration in bone blocks over 7 days indicated that neither agent was able to consistently reach levels in bone of >10% of the original dose. The model was, therefore, able to demonstrate the challenges posed by biofilm growth on and within bone. SIGNIFICANCE AND IMPACT OF THE STUDY: The majority of studies of antibiotic efficacy in the treatment of chronic osteomyelitis are carried out in animals. We developed an in vitro model of Staphylococcus aureus infection of bone to evaluate the ability of antibiotics to eradicate mature biofilms on surfaces analogous to necrotic bone. The results demonstrated the difficulties which occur in osteomyelitis treatment, with only very high concentrations of antibiotic able to penetrate the bone sufficiently to reduce bacterial survival whilst still failing to eradicate biofilms. This model could be of use in initial screening of novel compounds intended for use in the treatment of osteomyelitis.

Risk factors and prognosis of complicated urinary tract infections caused by Pseudomonas aeruginosa in hospitalized patients: a retrospective multicenter cohort study.

PURPOSE: Complicated urinary tract infections (cUTIs) are among the most frequent health-care-associated infections. In patients with cUTI, Pseudomonas aeruginosa deserves special attention, since it can affect patients with serious underlying conditions. Our aim was to gain insight into the risk factors and prognosis of P. aeruginosa cUTIs in a scenario of increasing multidrug resistance (MDR). METHODS: This was a multinational, retrospective, observational study at 20 hospitals in south and southeastern Europe, Turkey, and Israel including consecutive patients with cUTI hospitalized between January 2013 and December 2014. A mixed-effect logistic regression model was performed to assess risk factors for P. aeruginosa and MDR P. aeruginosa cUTI. RESULTS: Of 1,007 episodes of cUTI, 97 (9.6%) were due to P. aeruginosa. Resistance rates of P. aeruginosa were: antipseudomonal cephalosporins 35 of 97 (36.1%), aminoglycosides 30 of 97 (30.9%), piperacillin-tazobactam 21 of 97 (21.6%), fluoroquinolones 43 of 97 (44.3%), and carbapenems 28 of 97 (28.8%). The MDR rate was 28 of 97 (28.8%). Independent risk factors for P. aeruginosa cUTI were male sex (OR 2.61, 95% CI 1.60-4.27), steroid therapy (OR 2.40, 95% CI 1.10-5.27), bedridden functional status (OR 1.79, 95% CI 0.99-3.25), antibiotic treatment within the previous 30 days (OR 2.34, 95% CI 1.38-3.94), indwelling urinary catheter (OR 2.41, 95% CI 1.43-4.08), and procedures that anatomically modified the urinary tract (OR 2.01, 95% CI 1.04-3.87). Independent risk factors for MDR P. aeruginosa cUTI were age (OR 0.96, 95% CI 0.93-0.99) and anatomical urinary tract modification (OR 4.75, 95% CI 1.06-21.26). Readmission was higher in P. aeruginosa cUTI patients than in other etiologies (23 of 97 [23.7%] vs 144 of 910 [15.8%], P=0.04), while 30-day mortality was not significantly different (seven of 97 [7.2%] vs 77 of 910 [8.5%], P=0.6). CONCLUSION: Patients with P. aeruginosa cUTI had characteristically a serious baseline condition and manipulation of the urinary tract, although their mortality was not higher than that of patients with cUTI caused by other etiologies.

The role of whole genome sequencing in antimicrobial susceptibility testing of bacteria: report from the EUCAST Subcommittee.

Whole genome sequencing (WGS) offers the potential to predict antimicrobial susceptibility from a single assay. The European Committee on Antimicrobial Susceptibility Testing established a subcommittee to review the current development status of WGS for bacterial antimicrobial susceptibility testing (AST). The published evidence for using WGS as a tool to infer antimicrobial susceptibility accurately is currently either poor or non-existent and the evidence / knowledge base requires significant expansion. The primary comparators for assessing genotypic-phenotypic concordance from WGS data should be changed to epidemiological cut-off values in order to improve differentiation of wild-type from non-wild-type isolates (harbouring an acquired resistance). Clinical breakpoints should be a secondary comparator. This assessment will reveal whether genetic predictions could also be used to guide clinical decision making. Internationally agreed principles and quality control (QC) metrics will facilitate early harmonization of analytical approaches and interpretive criteria for WGS-based predictive AST. Only data sets that pass agreed QC metrics should be used in AST predictions. Minimum performance standards should exist and comparative accuracies across different WGS laboratories and processes should be measured. To facilitate comparisons, a single public database of all known resistance loci should be established, regularly updated and strictly curated using minimum standards for the inclusion of resistance loci. For most bacterial species the major limitations to widespread adoption for WGS-based AST in clinical laboratories remain the current high-cost and limited speed of inferring antimicrobial susceptibility from WGS data as well as the dependency on previous culture because analysis directly on specimens remains challenging. For most bacterial species there is currently insufficient evidence to support the use of WGS-inferred AST to guide clinical decision making. WGS-AST should be a funding priority if it is to become a rival to phenotypic AST. This report will be updated as the available evidence increases.

The Innovative Medicines Initiative's New Drugs for Bad Bugs programme: European public-private partnerships for the development of new strategies to tackle antibiotic resistance.

Antibiotic resistance (ABR) is a global public health threat. Despite the emergence of highly resistant organisms and the huge medical need for new drugs, the development of antibacterials has slowed to an unacceptable level worldwide. Numerous government and non-government agencies have called for public-private partnerships and innovative funding mechanisms to address this problem. To respond to this public health crisis, the Innovative Medicines Initiative Joint Undertaking programme has invested more than €660 million, with a goal of matched contributions from the European Commission and the European Federation of Pharmaceutical Industries and Associations, in the development of new antibacterial strategies. The New Drugs for Bad Bugs (ND4BB) programme, an Innovative Medicines Initiative, has the ultimate goal to boost the fight against ABR at every level from basic science and drug discovery, through clinical development to new business models and responsible use of antibiotics. Seven projects have been launched within the ND4BB programme to achieve this goal. Four of them will include clinical trials of new anti-infective compounds, as well as epidemiological studies on an unprecedented scale, which will increase our knowledge of ABR and specific pathogens, and improve the designs of the clinical trials with new investigational drugs. The need for rapid concerted action has driven the funding of seven topics, each of which should add significantly to progress in the fight against ABR. ND4BB unites expertise and provides a platform where the commitment and resources required by all parties are streamlined into a joint public-private partnership initiative of unprecedented scale.

The global threat of antimicrobial resistance: science for intervention.

In the last decade we have witnessed a dramatic increase in the proportion and absolute number of bacterial pathogens resistant to multiple antibacterial agents. Multidrug-resistant bacteria are currently considered as an emergent global disease and a major public health problem. The B-Debate meeting brought together renowned experts representing the main stakeholders (i.e. policy makers, public health authorities, regulatory agencies, pharmaceutical companies and the scientific community at large) to review the global threat of antibiotic resistance and come up with a coordinated set of strategies to fight antimicrobial resistance in a multifaceted approach. We summarize the views of the B-Debate participants regarding the current situation of antimicrobial resistance in animals and the food chain, within the community and the healthcare setting as well as the role of the environment and the development of novel diagnostic and therapeutic strategies, providing expert recommendations to tackle the global threat of antimicrobial resistance.

Widespread implementation of EUCAST breakpoints for antibacterial susceptibility testing in Europe.

The European Committee on Antimicrobial Susceptibility Testing (EUCAST) was established to harmonise clinical antimicrobial breakpoints and to define breakpoints for new agents in Europe. Data from the European Antimicrobial Resistance Surveillance Network (EARS-Net) external quality assessment (EQA) exercises from 2009 to 2012, from the United Kingdom External Quality Assessment Scheme (UK NEQAS) from November 2009 to March 2013 and data collected by EUCAST through a questionnaire in the first quarter of 2013 were analysed to investigate implementation of EUCAST guidelines in Europe. A rapid change to use of EUCAST breakpoints was observed over time. Figures for implementation of EUCAST breakpoints at the end of the studied period were 61.2% from EARSNet data and 73.2% from UK NEQAS data. Responses to the EUCAST questionnaire indicated that EUCAST breakpoints were used by over 50% of laboratories in 18 countries, by 10 to 50% of laboratories in eight countries and by less than 10% in seven countries. The EUCAST disk diffusion method was used by more than 50% of laboratories in 12 countries, by 10 to 50% of laboratories in ten countries and by less than 10% in eleven countries. EUCAST guidelines implementation is essential to ensure consistent clinical reporting of antimicrobial susceptibility results and antimicrobial resistance surveillance.

A systematic review of matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry compared to routine microbiological methods for the time taken to identify microbial organisms from positive blood cultures.

Bloodstream infections are a significant source of mortality and morbidity. Patient outcomes are improved by rapid identification of the causative pathogen and administration of appropriate antimicrobial therapy. Matrix-assisted laser desorption/ionisation time-of-flight (MALDI-TOF) mass spectrometry has recently emerged as an alternative to microbiological identification. It is important to establish whether the costs of MALDI-TOF are justified by more timely identification and appropriate therapy, reduced length of stay and reduced hospital costs. We undertook a systematic review of the literature comparing MALDI-TOF and routine methods for the identification of the aetiological agent in patients with known or suspected bloodstream infection. The primary outcome of the review was the 'time to identify' organisms. Information on related measures such as 'time to appropriate antimicrobial treatment' and downstream hospital cost was also collected where reported. Ten of 775 articles identified met the inclusion criteria. All included studies were observational. MALDI-TOF identification was at least 24 h faster than routine methods in most circumstances. MADLI-TOF was associated with a reduction in downstream hospital costs and length of stay in studies reporting these outcomes. The observational studies reviewed provide evidence of potentially substantial time savings of MALDI-TOF in pathogen identification and instigation of appropriate therapy, which may also reduce hospital stay. Due to the small number of studies, all at relatively high risk of bias, this cannot be considered as definitive evidence of the impact of MALDI-TOF. More and better evidence, including impact on patient health and cost-effectiveness, is required.

Corrigendum to "The global threat of antimicrobial resistance: science for intervention" [New Microbes New Infect 6 (2015): 22-29].

[This corrects the article DOI: 10.1016/j.nmni.2015.02.007.].

Viral infections in pregnancy: advice for healthcare workers.

BACKGROUND: Healthcare workers (HCWs) have the potential for increased exposure to infectious disease resulting from the provision of patient care. Pregnancy can confer specific problems in some infections for the mother and her unborn child. AIMS: To discuss the viral infections encountered in the UK that constitute a particular risk to the pregnant HCW: human immunodeficiency virus, hepatitis B virus, hepatitis C virus, varicella-zoster virus, herpes simplex virus, human parvovirus B19, cytomegalovirus, rubella, measles, enteroviruses, mumps and influenza. Evidence for nosocomial transmission, clinical aspects specific to pregnancy, and recommendations to protect the pregnant HCW at work are included. METHODS: Medline, EMBASE and Pubmed were searched using a list of keywords specific to each viral infection, including 'nosocomial', 'occupational' and 'healthcare workers'. References from the bibliographies of articles identified were reviewed for relevant material. FINDINGS: The evidence for increased risk in the healthcare setting for many of these infections, outside of outbreaks, is weak, possibly because of the application of standard protective infection control measures or because risk of community exposure is greater. The pregnant HCW should be advised on protective behaviour in both settings. Potential interventions include vaccination and reducing the likelihood of exposure through universal precautions, infection control and redeployment. CONCLUSION: Protection of the pregnant HCW is the responsibility of the individual, antenatal care provider and employer, and is made possible through awareness of the risks and potential interventions both before and after exposure. If exposure occurs or if the HCW develops an infective illness, urgent specialist advice is required.

Comparative antibacterial effects of moxifloxacin and levofloxacin on Streptococcus pneumoniae strains with defined mechanisms of resistance: impact of bacterial inoculum.

OBJECTIVES: We aim to further define the impact of the mechanism of fluoroquinolone resistance and inoculum load on the pharmacodynamic effects of levofloxacin and moxifloxacin on Streptococcus pneumoniae. METHODS: The antibacterial effects of and emergence of resistance (EoR) to moxifloxacin (400 mg once daily) or levofloxacin (750 mg once daily or 500 mg twice daily) were compared using five S. pneumoniae strains containing no known resistance mechanisms, efflux resistance mechanisms, a parC mutation or parC and gyrA mutations, at high (10(8) cfu/mL) and low (10(6) cfu/mL) inocula. An in vitro pharmacokinetic model was used and simulations were performed over 96 h. After drug exposure, isolates were tested for the presence of efflux pumps and mutations in the quinolone resistance-determining regions. RESULTS: A high inoculum diminished the antibacterial effect of moxifloxacin and levofloxacin. Levofloxacin at both dosages produced EoR with all strains. Levofloxacin regimens with AUC/MIC ratios <100 produced EoR. Moxifloxacin produced EoR with the parC strain only. CONCLUSIONS: Levofloxacin dosing regimens with low AUC/MIC ratios select for efflux pump overexpression, leading to fluoroquinolone resistance. Levofloxacin dosing may select for gyrA mutations, inducing moxifloxacin resistance. These data confirm that a fluoroquinolone AUC/MIC ratio of >100 is required for prevention of EoR.

EUCAST expert rules in antimicrobial susceptibility testing.

EUCAST expert rules have been developed to assist clinical microbiologists and describe actions to be taken in response to specific antimicrobial susceptibility test results. They include recommendations on reporting, such as inferring susceptibility to other agents from results with one, suppression of results that may be inappropriate, and editing of results from susceptible to intermediate or resistant or from intermediate to resistant on the basis of an inferred resistance mechanism. They are based on current clinical and/or microbiological evidence. EUCAST expert rules also include intrinsic resistance phenotypes and exceptional resistance phenotypes, which have not yet been reported or are very rare. The applicability of EUCAST expert rules depends on the MIC breakpoints used to define the rules. Setting appropriate clinical breakpoints, based on treating patients and not on the detection of resistance mechanisms, may lead to modification of some expert rules in the future.