Publications by authors named "Heiman F L Wertheim"

109 Publications

Genome-wide analysis in unravels a high level of genetic homoplasy associated with cefotaxime resistance.

Microb Genom 2021 Apr;7(4)

Centre for Molecular and Biomolecular Informatics, Radboud University Medical Center, Nijmegen, The Netherlands.

Cefotaxime (CTX) is a third-generation cephalosporin (3GC) commonly used to treat infections caused by . Two genetic mechanisms have been associated with 3GC resistance in . The first is the conjugative transfer of a plasmid harbouring antibiotic-resistance genes. The second is the introduction of mutations in the promoter region of the β-lactamase gene that cause chromosome-encoded β-lactamase hyperproduction. A wide variety of promoter mutations related to AmpC hyperproduction have been described. However, their link to CTX resistance has not been reported. We recultured 172 cefoxitin-resistant isolates with known CTX minimum inhibitory concentrations and performed genome-wide analysis of homoplastic mutations associated with CTX resistance by comparing Illumina whole-genome sequencing data of all isolates to a PacBio sequenced reference chromosome. We mapped the mutations on the reference chromosome and determined their occurrence in the phylogeny, revealing extreme homoplasy at the -42 position of the promoter. The 24 occurrences of a T at the -42 position rather than the wild-type C, resulted from 18 independent C>T mutations in five phylogroups. The -42 C>T mutation was only observed in lacking a plasmid-encoded gene. The association of the -42 C>T mutation with CTX resistance was confirmed to be significant (false discovery rate <0.05). To conclude, genome-wide analysis of homoplasy in combination with CTX resistance identifies the -42 C>T mutation of the promotor as significantly associated with CTX resistance and underlines the role of recurrent mutations in the spread of antibiotic resistance.
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http://dx.doi.org/10.1099/mgen.0.000556DOI Listing
April 2021

Community-based antibiotic access and use in six low-income and middle-income countries: a mixed-method approach.

Lancet Glob Health 2021 May 10;9(5):e610-e619. Epub 2021 Mar 10.

MRC-Wits Rural Public Health and Health Transitions Research Unit (Agincourt), University of the Witwatersrand, Johannesburg, South Africa.

Background: Antimicrobial misuse is common in low-income and middle-income countries (LMICs), and this practice is a driver of antibiotic resistance. We compared community-based antibiotic access and use practices across communities in LMICs to identify contextually specific targets for interventions to improve antibiotic use practices.

Methods: We did quantitative and qualitative assessments of antibiotic access and use in six LMICs across Africa (Mozambique, Ghana, and South Africa) and Asia (Bangladesh, Vietnam, and Thailand) over a 2·5-year study period (July 1, 2016-Dec 31, 2018). We did quantitative assessments of community antibiotic access and use through supplier mapping, customer exit interviews, and household surveys. These quantitative assessments were triangulated with qualitative drug supplier and consumer interviews and discussions.

Findings: Vietnam and Bangladesh had the largest proportions of non-licensed antibiotic dispensing points. For mild illness, drug stores were the most common point of contact when seeking antibiotics in most countries, except South Africa and Mozambique, where public facilities were most common. Self-medication with antibiotics was found to be widespread in Vietnam (55·2% of antibiotics dispensed without prescription), Bangladesh (45·7%), and Ghana (36·1%), but less so in Mozambique (8·0%), South Africa (1·2%), and Thailand (3·9%). Self-medication was considered to be less time consuming, cheaper, and overall, more convenient than accessing them through health-care facilities. Factors determining where treatment was sought often involved relevant policies, trust in the supplier and the drug, disease severity, and whether the antibiotic was intended for a child. Confusion regarding how to identify oral antibiotics was revealed in both Africa and Asia.

Interpretation: Contextual complexities and differences between countries with different incomes, policy frameworks, and cultural norms were revealed. These contextual differences render a single strategy inadequate and instead necessitate context-tailored, integrated intervention packages to improve antibiotic use in LMICs as part of global efforts to combat antibiotic resistance.

Funding: Wellcome Trust and Volkswagen Foundation.
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http://dx.doi.org/10.1016/S2214-109X(21)00024-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050200PMC
May 2021

Comparative Performance Testing of Respirator versus Surgical Mask Using a Water Droplet Spray Model.

Int J Environ Res Public Health 2021 02 8;18(4). Epub 2021 Feb 8.

Department of Medical Microbiology, Radboudumc, 6500 HB Nijmegen, The Netherlands.

Background: During the SARS-CoV-2 pandemic, there was shortage of the standard respiratory protective equipment (RPE). The aim of this study was to develop a procedure to test the performance of alternative RPEs used in the care of COVID-19 patients.

Methods: A laboratory-based test was developed to compare RPEs by total inward leakage (TIL). We used a crossflow nebulizer to produce a jet spray of 1-100 µm water droplets with a fluorescent marker. The RPEs were placed on a dummy head and sprayed at distances of 30 and 60 cm. The outcome was determined as the recovery of the fluorescent marker on a membrane filter placed on the mouth of the dummy head.

Results: At 30 cm, a type IIR surgical mask gave a 17.7% lower TIL compared with an FFP2 respirator. At 60 cm, this difference was similar, with a 21.7% lower TIL for the surgical mask compared to the respirator. When adding a face shield, the TIL at 30 cm was further reduced by 9.5% for the respirator and 16.6% in the case of the surgical mask.

Conclusions: A safe, fast and very sensitive test method was developed to assess the effectiveness of RPE by comparison under controlled conditions.
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http://dx.doi.org/10.3390/ijerph18041599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915861PMC
February 2021

The Benzimidazole SPR719 Shows Promising Concentration-Dependent Activity and Synergy against Nontuberculous Mycobacteria.

Antimicrob Agents Chemother 2021 03 18;65(4). Epub 2021 Mar 18.

Radboudumc Center for Infectious Diseases, Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, the Netherlands

Nontuberculous mycobacterial pulmonary disease (NTM-PD) is emerging worldwide. Currently recommended multidrug treatment regimens yield poor outcomes, and new drugs and regimens are direly needed. SPR719, the active moiety of SPR720, is a new benzimidazole antibiotic with limited data on antimycobacterial activity. We determined MICs and MBCs against 138 clinical and reference strains of complex (MAC), , , , , and and determined synergy with antimycobacterial drugs by checkerboard titrations. To study pharmacodynamics, we performed time-kill kinetics assays of SPR719 alone and in combinations against , , and and assessed synergy by response surface analysis according to Bliss independence. SPR719 showed potent activity against MAC (MIC, 2 mg/liter) and (MIC, 0.125 mg/liter) and modest activity against (MIC, 8 mg/liter); its activity is bacteriostatic and concentration-dependent. We recorded a potential for combination therapy with ethambutol against and and synergy with clarithromycin against Ethambutol increased the SPR719 kill rate against but only prevented SPR719 resistance in SPR719 is active against NTM; its activity is strongest against , followed by MAC and SPR719 shows promise for combination therapy with ethambutol against MAC and and synergy with clarithromycin against The parent drug SPR720 could have a role especially in MAC pulmonary disease treatment. Further studies in dynamic models and trials are ongoing to advance clinical development.
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http://dx.doi.org/10.1128/AAC.02469-20DOI Listing
March 2021

Antibiotic use and prescription and its effects on Enterobacteriaceae in the gut in children with mild respiratory infections in Ho Chi Minh City, Vietnam. A prospective observational outpatient study.

PLoS One 2020 4;15(11):e0241760. Epub 2020 Nov 4.

Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.

Background And Objectives: Treatment guidelines do not recommend antibiotic use for acute respiratory infections (ARI), except for streptococcal pharyngitis/tonsillitis and pneumonia. However, antibiotics are prescribed frequently for children with ARI, often in absence of evidence for bacterial infection. The objectives of this study were 1) to assess the appropriateness of antibiotic prescriptions for mild ARI in paediatric outpatients in relation to available guidelines and detected pathogens, 2) to assess antibiotic use on presentation using questionnaires and detection in urine 3) to assess the carriage rates and proportions of resistant intestinal Enterobacteriaceae before, during and after consultation.

Materials And Methods: Patients were prospectively enrolled in Children's Hospital 1, Ho Chi Minh City, Vietnam and diagnoses, prescribed therapy and outcome were recorded on first visit and on follow-up after 7 days. Respiratory bacterial and viral pathogens were detected using molecular assays. Antibiotic use before presentation was assessed using questionnaires and urine HPLC. The impact of antibiotic usage on intestinal Enterobacteriaceae was assessed with semi-quantitative culture on agar with and without antibiotics on presentation and after 7 and 28 days.

Results: A total of 563 patients were enrolled between February 2009 and February 2010. Antibiotics were prescribed for all except 2 of 563 patients. The majority were 2nd and 3rd generation oral cephalosporins and amoxicillin with or without clavulanic acid. Respiratory viruses were detected in respiratory specimens of 72.5% of patients. Antibiotic use was considered inappropriate in 90.1% and 67.5%, based on guidelines and detected pathogens, respectively. On presentation parents reported antibiotic use for 22% of patients, 41% of parents did not know and 37% denied antibiotic use. Among these three groups, six commonly used antibiotics were detected with HPLC in patients' urine in 49%, 40% and 14%, respectively. Temporary selection of 3rd generation cephalosporin resistant intestinal Enterobacteriaceae during antibiotic use was observed, with co-selection of resistance to aminoglycosides and fluoroquinolones.

Conclusions: We report overuse and overprescription of antibiotics for uncomplicated ARI with selection of resistant intestinal Enterobacteriaceae, posing a risk for community transmission and persistence in a setting of a highly granular healthcare system and unrestricted access to antibiotics through private pharmacies.

Registration: This study was registered at the International Standard Randomised Controlled Trials Number registry under number ISRCTN32862422: http://www.isrctn.com/ISRCTN32862422.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241760PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641406PMC
December 2020

Eradication of Staphylococcus aureus colonization by chronic use of mupirocin in patients on home parenteral nutrition.

Nutrition 2021 01 29;81:110985. Epub 2020 Aug 29.

Intestinal Failure Unit, Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, the Netherlands.

Objectives: Although in other groups Staphylococcus aureus eradication has proven to be an effective infection prevention measure, to our knowledge, no such studies have been performed in patients on home parenteral nutrition (HPN). The aim of this study was to investigate the efficacy of chronic nasal mupirocin use on S. aureus eradication and prevention of catheter related infections in patients on HPN.

Methods: This was a cohort study with data collected from adult patients on HPN who were screened for S. aureus carriage. In case of carriage, the patient was instructed to apply mupirocin nasal ointment monthly. Outcomes were the percentage of successful S. aureus eradication and the effect on the incidence of catheter-related infections and development of mupirocin resistance.

Results: S. aureus nasal carriage was found in 54% of the patients. Eradication was successful in 66% (70 of 106) of patients treated with mupirocin. Overall S. aureus catheter-related infection rates decreased by 50% (P = 0.02). The decrease was mostly due to a drop in central line-associated bloodstream infection (CLABSI) rates (0.26versus 0.1 per 1000 central venous catheter days; P = 0.04). The overall CLABSI rates decreased as well (incidence ratio rate, 0.43; 95% confidence interval. 0.24-0.76; P < 0.01). Low-level mupirocin resistance was observed in four patients.

Conclusions: Findings from the present study highlighted the potential usefulness of mupirocin ointment prophylaxis to establish S. aureus eradication in patients on HPN. However, awareness for the development of mupirocin resistance is prudent. Further research needs to be carried out to validate these findings.
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http://dx.doi.org/10.1016/j.nut.2020.110985DOI Listing
January 2021

Community-level consumption of antibiotics according to the AWaRe (Access, Watch, Reserve) classification in rural Vietnam.

JAC Antimicrob Resist 2020 Sep 14;2(3):dlaa048. Epub 2020 Sep 14.

Oxford University Clinical Research Unit, Hanoi Unit, Hanoi, Vietnam.

Objectives: To review community-level consumption of antibiotics in rural Vietnam, according to the WHO Access, Watch, Reserve (AWaRe) classification of 2019, and identify factors associated with the choice of these antibiotics.

Methods: In this cross-sectional study, data on antibiotic purchases were collected through a customer exit survey of 20 community antibiotic suppliers in Ba Vi District, Hanoi, between September 2017 and July 2018. Antibiotic consumption was estimated through the number of antibiotic encounters, the number of DDDs supplied and the number of treatment days (DOTs) with antibiotics, and analysed according to the AWaRe classification. The factors associated with watch-group antibiotic supply were identified through multivariable logistic regression analysis.

Results: In total, there were 1342 antibiotic encounters, with access-group antibiotics supplied in 792 encounters (59.0%), watch-group antibiotics supplied in 527 encounters (39.3%) and not-recommended antibiotics supplied in 23 encounters (1.7%). No reserve-group antibiotics were supplied. In children, the consumption of watch-group antibiotics dominated in all three measures (54.8% of encounters, 53.0% of DOTs and 53.6% of DDDs). Factors associated with a higher likelihood of watch-group antibiotic supply were: private pharmacy (OR, 4.23; 95% CI, 2.8-6.38; <0.001), non-prescription antibiotic sale (OR, 2.62; 95% CI, 1.78-3.87; <0.001) and children (OR, 2.56; 95% CI, 1.84-3.55; <0.001).

Conclusions: High consumption of watch-group antibiotics was observed, especially for use in children. The frequent supply of watch-group antibiotics at private pharmacies reconfirms the need for implementing pharmacy-targeted interventions in Vietnam.
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http://dx.doi.org/10.1093/jacamr/dlaa048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497401PMC
September 2020

Every medicine is medicine; exploring inappropriate antibiotic use at the community level in rural Ghana.

BMC Public Health 2020 Jul 14;20(1):1103. Epub 2020 Jul 14.

Radboud University Medical Centre, Department of Medical Microbiology and Radboudumc Center for Infectious Diseases, Nijmegen, Netherlands.

Background: Inappropriate antibiotic use is an important driver of antibiotic resistance. This study sought to explore inappropriate antibiotic use and confusing antibiotics with other medicines in Ghana using ethnomethodology research approach.

Methods: This was an explorative study involving 15 in-depth interviews among health professionals and private dispensers and eight focus group discussions among 55 community members. Qualitative data were coded using Nvivo 12, thematically analysed and presented as narratives with quotes to support the findings.

Results: Self-medication was common and antibiotics were used to treat specific diseases but respondents were not aware these were 'antibiotics'. Various antibiotics were used for indications that in principle do not require systemic antibiotics, like stomach ache and sores on the body. Antibiotics, in particular tetracycline and metronidazole, were poured into "akpeteshie" (local gin) to treat hernia and perceived stomach sores (stomach ulcer). These practices were copied/learnt from various sources like over-the-counter medicine sellers, family, friends, radio/television, drug peddlers, pharmacies and doctors. Medicines in capsules were referred to as 'topaye' or 'abombelt' in Twi (local dialect) and perceived to treat pain associated with diseases. Antibiotics in capsules were described with colours which appeared confusing as some capsules with different drugs in them have similar colours.

Conclusion: Inappropriate antibiotic use were influenced by general lack of knowledge on antibiotics and identification of antibiotics by colours of capsules which leads to confusion and could lead to inappropriate antibiotic use. There is the need for public health education on appropriate antibiotic use and standardization of appearance of antibiotics and other drugs to optimize use.
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http://dx.doi.org/10.1186/s12889-020-09204-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359511PMC
July 2020

Recovery of aerobic gram-negative bacteria from the Copan Eswab transport system after long-term storage.

Diagn Microbiol Infect Dis 2020 Sep 6;98(1):115100. Epub 2020 Jun 6.

Radboudumc Center for Infectious Diseases, Department of Medical Microbiology, Radboud university medical center, Nijmegen, The Netherlands. Electronic address:

We evaluated the Copan Eswab transport system for the quantitative recovery of Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa after 1, 2, 3, 5, and 7 days of storage at room and refrigerator temperatures, and 7 and 30 days of storage at -80 °C and -20 °C using mono- and polymicrobial samples. The study was based on Clinical and Laboratory Standards Institute (CLSI) M40-A2 standard procedures on the quality control of microbiological transport systems. Eswab met the CLSI standards at room and refrigerator temperatures for all (combinations of) bacterial strains tested. At room temperature, after 24 h, bacterial growth was observed. At -80 °C, bacterial viability was maintained in monomicrobial samples; however, in polymicrobial samples, P. aeruginosa recovery was compromised. Storage at -20 °C was unsuitable. We conclude that specimens collected using Eswab should be transported to the laboratory as soon as possible. If transport or processing is delayed, specimens should preferably be stored at refrigerator temperatures.
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http://dx.doi.org/10.1016/j.diagmicrobio.2020.115100DOI Listing
September 2020

Influenza A(H1N1)pdm09 but not A(H3N2) virus infection induces durable sero-protection: results from the Ha Nam Cohort.

J Infect Dis 2020 Jun 2. Epub 2020 Jun 2.

Oxford University Clinical Research Unit and Wellcome Trust Major Overseas Programme, Hanoi, Viet Nam.

Background: The extent to which influenza recurrence depends upon waning immunity from prior-infection is undefined. We used antibody titres of Ha-Nam cohort participants to estimate protection curves and decay trajectories.

Methods: 270 households participated in influenza-like-illness surveillance and provided blood at intervals spanning RTPCR-confirmed transmission. Sera were tested in haemagglutination inhibition assay. Infection was defined as RTPCR+ influenza-like-illness and/or seroconversion. Median protective titres were estimated using scaled-logistic-regression to model pre-transmission titre against infection status in that season, limiting analysis to households with infection(s). Titres were modelled against month since infection using mixed-effects linear regression to estimate decay and when titres fell below protection-thresholds.

Results: 295 and 314 participants were infected with H1N1pdm09-like and A/Perth/16/09-like (H3N2Pe09) viruses, respectively between December 2008-2012. The proportion of householders not-infected (protected) rose more steeply with titre for H1N1pdm09 than for H3N2Pe09, and estimated 50% protection titres were 19.6 and 37.3, respectively. Post-infection titres started higher against H3N2Pe09 but decayed more steeply than against H1N1pdm09. Sero-protection was estimated to be sustained against H1N1pdm09 but to wane by 8-months for H3N2Pe09.

Conclusions: Estimates indicate that infection induces durable sero-protection against H1N1pdm09 but not H3N2Pe09, which could in part account for the younger age of A(H1N1) versus A(H3N2) cases.
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http://dx.doi.org/10.1093/infdis/jiaa293DOI Listing
June 2020

Efficacy and safety of selective decontamination of the digestive tract (SDD) to prevent recurrent hepatic cyst infections in polycystic liver disease: a retrospective case series.

J Antimicrob Chemother 2020 09;75(9):2666-2669

Department of Gastroenterology and Hepatology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands.

Background: Hepatic cyst infection is a complication of polycystic liver disease (PLD) that causes substantial morbidity. Repetitive infection is frequent and is increasingly difficult to treat. As translocated gut bacteria are considered the cause, we hypothesize that selective decontamination of the digestive tract (SDD) reduces recurrence of hepatic cyst infection.

Methods: We performed a retrospective, observational study in two referral centres. All patients with PLD treated with SDD for hepatic cyst infection were included. Efficacy was determined by calculating the infection incidence (hepatic cyst infections per month) before and during SDD therapy. Adverse events were scored according to the Common Terminology Criteria for Adverse Events (CTCAE).

Results: We identified eight patients who received SDD (88% female, 88% polycystic kidney disease). The median age was 65 years (IQR: 51-74 years). SDD lowered the median incidence from 0.09 episodes per month (IQR: 0.06-0.25 episodes per month) to 0.01 episodes per month (IQR: 0.00-0.05 episodes per month) (P = 0.12). Discontinuation of SDD led to rapid recurrence of cyst infection (71% within 6 weeks). SDD consisted of polymyxins with/without aminoglycosides. The median SDD treatment duration was 20 months (range: 3-89 months). Six patients (75%) developed adverse events [CTCAE Grade 1 (gastrointestinal: n = 3) or Grade 3 (ototoxicity: n = 1; fungal infection: n = 1)], mostly attributable to aminoglycosides; one patient developed polymyxin E resistance.

Conclusions: SDD prophylaxis provides a novel strategy for limiting recurrent hepatic cyst infection in PLD patients. However, adverse events are frequent and curtail its use. As most were attributable to aminoglycosides, polymyxin E is considered the preferred therapy.
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http://dx.doi.org/10.1093/jac/dkaa186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443730PMC
September 2020

Thioridazine Is an Efflux Pump Inhibitor in Mycobacterium avium Complex but of Limited Clinical Relevance.

Antimicrob Agents Chemother 2020 06 23;64(7). Epub 2020 Jun 23.

Radboud Center for Infectious Diseases, Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands

Treatment of complex pulmonary disease (MAC-PD) is challenging partly due to high efflux pump expression. Thioridazine might block these efflux pumps. We explore the efficacy of thioridazine against isolates using MICs, time-kill combination assays, macrophage infection assays, and efflux assays. Thioridazine is bactericidal against , inhibits intracellular growth at 2× MIC, and blocks ethidium bromide efflux. However, its toxicity and low plasma concentrations make it unlikely to add efficacy to MAC-PD therapy.
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http://dx.doi.org/10.1128/AAC.00181-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318027PMC
June 2020

Inhaled tigecycline is effective against Mycobacterium abscessus in vitro and in vivo.

J Antimicrob Chemother 2020 07;75(7):1889-1894

Radboudumc Center for Infectious Diseases, Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.

Background: Mycobacterium abscessus causes chronic pulmonary infections. Owing to its resistance to most classes of antibiotics, treatment is complex and cure rates are only 45%. Tigecycline is active against M. abscessus, but severe toxicity and the need for IV administration limit its use.

Objectives: To assess the potential of inhaled tigecycline as a treatment for M. abscessus pulmonary disease, by measuring its efficacy in a mouse model of chronic M. abscessus pulmonary disease, establishing the intracellular activity of tigecycline against M. abscessus in human macrophages and measuring the activity of tigecycline in the sputum of cystic fibrosis patients.

Methods: We infected GM-CSF knockout mice with M. abscessus by intrapulmonary aerosol. Infected mice were treated with tigecycline in 0.25, 1.25 and 2.5 mg doses, by inhalation, or untreated, for 28 days. Tigecycline was added to human peripheral blood-derived macrophages infected with M. abscessus to assess its intracellular activity. We performed a time-kill kinetics experiment of tigecycline against M. abscessus with and without sputum of cystic fibrosis patients.

Results: Inhaled tigecycline proved highly effective against M. abscessus in GM-CSF knockout mice. The effect was dose dependent. Tigecycline showed potent activity against M. abscessus in macrophages and retained most of its activity in the presence of sputum of cystic fibrosis patients.

Conclusions: Inhaled tigecycline may represent a viable treatment option for M. abscessus pulmonary disease, where treatment outcomes are currently very poor. A stable and safe formulation is required to proceed to further pharmacodynamic studies and ultimately clinical trials.
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http://dx.doi.org/10.1093/jac/dkaa110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778363PMC
July 2020

Determinants of Inappropriate Antibiotics Use in Rural Central Ghana Using a Mixed Methods Approach.

Front Public Health 2020 24;8:90. Epub 2020 Mar 24.

Kintampo Health Research Centre, Ghana Health Service, Kintampo, Ghana.

The consequences of antibiotic resistance are projected to be most severe in low and middle income countries with high infectious disease burden. This study examined determinants of inappropriate antibiotic use at the community level in rural Ghana. An observational study involving qualitative and quantitative methods was conducted between July, 2016 and September, 2018 in Ghana. Two household surveys were conducted at two time points (2017 and 2018) among 1,100 randomly selected households over 1 year. The surveys focused on antibiotic use episodes in the past month. Four in-depth interviews and two focus group discussions were performed to further explain the survey results. Determinants of inappropriate antibiotic use were assessed using a mixed effect logistic regression analysis (multilevel analysis) to account for the clustered nature of data. We defined inappropriate antibiotic use as either use without prescription, not completing treatment course or non-adherence to instruction for use. Qualitative data were thematically analyzed. A total of 1,100 households was enrolled in which antibiotics were used in 585 (53.2%) households in the month prior to the surveys. A total of 676 (21.2%) participants out of 3,193 members from the 585 reportedly used antibiotics for 761 episodes of illness. Out of the 761 antibiotic use episodes, 659 (86.6%) were used inappropriately. Paying for healthcare without health insurance (Odds Ratio (OR): 2.10, 95% CI: 1.1-7.4, -value: 0.026), not seeking healthcare from health centers (OR: 2.4, 95% CI: 1.2-5.0, -value: 0.018), or pharmacies (OR: 4.6, 95% CI: 1.7-13.0, -value: 0.003) were significantly associated with inappropriate antibiotic use. Socio-demographic characteristics were not significantly associated with inappropriate antibiotic use. However, the qualitative study described the influence of cost of medicines on inappropriate antibiotic use. It also revealed that antibiotic users with low socioeconomic status purchased antibiotics in installments which, could facilitate inappropriate use. Inappropriate antibiotic use was high and influenced by out-of-pocket payment for healthcare, seeking healthcare outside health centers, pharmacies, and buying antibiotics in installments due to cost. To improve appropriate antibiotic use, there is the need for ministry of health and healthcare agencies in Ghana to enhance healthcare access and healthcare insurance, and to provide affordable antibiotics.
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http://dx.doi.org/10.3389/fpubh.2020.00090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105730PMC
March 2020

Prostate biopsy techniques and pre-biopsy prophylactic measures: variation in current practice patterns in the Netherlands.

BMC Urol 2020 Mar 12;20(1):24. Epub 2020 Mar 12.

Department of Urology, Radboudumc, Nijmegen, the Netherlands.

Background: The clinical landscape of prostate biopsy (PB) is evolving with changes in procedures and techniques. Moreover, antibiotic resistance is increasing and influences the efficacy of pre-biopsy prophylactic regimens. Therefore, increasing antibiotic resistance may impact on clinical care, which probably results in differences between hospitals. The objective of our study is to determine the (variability in) current practices of PB in the Netherlands and to gain insight into Dutch urologists' perceptions of fluoroquinolone resistance and biopsy related infections.

Methods: An online questionnaire was prepared using SurveyMonkey® platform and distributed to all 420 members of the Dutch Association of Urology, who work in 81 Dutch hospitals. Information about PB techniques and periprocedural antimicrobial prophylaxis was collected. Urologists' perceptions regarding pre-biopsy antibiotic prophylaxis in an era of antibiotic resistance was assessed. Descriptive statistical analysis was performed.

Results: One hundred sixty-one responses (38.3%) were analyzed representing 65 (80.3%) of all Dutch hospitals performing PB. Transrectal ultrasound guided prostate biopsy (TRUSPB) was performed in 64 (98.5%) hospitals. 43.1% of the hospitals (also) used other image-guided biopsy techniques. Twenty-three different empirical prophylactic regimens were reported among the hospitals. Ciprofloxacin was most commonly prescribed (84.4%). The duration ranged from one pre-biopsy dose (59.4%) to 5 days extended prophylaxis. 25.2% of the urologists experienced ciprofloxacin resistance as a current problem in the prevention of biopsy related infections and 73.6% as a future problem.

Conclusions: There is a wide variation in practice patterns among Dutch urologists. TRUSPB is the most commonly used biopsy technique, but other image-guided biopsy techniques are increasingly used. Antimicrobial prophylaxis is not standardized and prolonged prophylaxis is common. The wide variation in practice patterns and lack of standardization underlines the need for evidence-based recommendations to guide urologists in choosing appropriate antimicrobial prophylaxis for PB in the context of increasing antibiotic resistance.
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http://dx.doi.org/10.1186/s12894-020-00592-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066741PMC
March 2020

Impact of the BioFire FilmArray gastrointestinal panel on patient care and infection control.

PLoS One 2020 6;15(2):e0228596. Epub 2020 Feb 6.

Department of Medical Microbiology & Radboudumc Center for Infectious Diseases, Radboud university medical center, Nijmegen, The Netherlands.

Objectives: Conventional routine PCR testing for gastrointestinal infections is generally based on pathogen related panels specifically requested by clinicians and can be erroneous and time consuming. The BioFire FilmArray gastrointestinal (GI) panel combines 22 pathogens into a single cartridge-based test on a random-access system, thereby reducing the turnaround time to less than 2 hours. We described the clinical impact of implementing the BioFire FilmArray on patients with gastroenteritis in our hospital.

Methods: Patients attending a Dutch tertiary care center (Radboud University Medical Center), from whom stool samples were obtained, were eligible for inclusion. The clinicians selected one or a combination of different routinely performed PCR panels (bacterial panel, viral panel, clostridium testing, and three parasitic panels) based on clinical history and symptoms. All samples were in parallel tested with the FilmArray. We retrospectively collected patient data regarding infection control and patient management to assess the potential impact of implementing the FilmArray.

Results: In total 182 patients were included. Routine PCR detected one or more pathogens in 52 (28.6%) patients compared to 72 (39.6%) using the FilmArray. Turnaround time (including transport) decreased from median 53 hours for the routine PCR to 16 hours for the FilmArray. Twenty-six patients could have been removed from isolation 29 hours sooner, 3.6 antibiotic days could have been saved and in five patients additional imaging testing (including colonoscopies) could have been prevented.

Conclusion: The theoretical implementation of the BioFire FilmArray GI panel in patients with clinical suspicion of gastroenteritis resulted in a significant better patient management.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228596PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004333PMC
May 2020

Is there a role for tedizolid in the treatment of non-tuberculous mycobacterial disease?

J Antimicrob Chemother 2020 03;75(3):609-617

Radboudumc Center for Infectious Diseases, Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.

Background: Pulmonary infections caused by non-tuberculous mycobacteria (NTM) are hard to treat and have low cure rates despite intensive multidrug therapy.

Objectives: To assess the feasibility of tedizolid, a new oxazolidinone, for the treatment of Mycobacterium avium and Mycobacterium abscessus.

Methods: We determined MICs of tedizolid for 113 isolates of NTM. Synergy with key antimycobacterial drugs was assessed using the chequerboard method and calculation of the FIC index (FICI). We performed time-kill kinetics assays of tedizolid alone and combined with amikacin for M. abscessus and with ethambutol for M. avium. Human macrophages were infected with M. abscessus and M. avium and subsequently treated with tedizolid; intracellular and extracellular cfu were quantified over time.

Results: NTM isolates generally had a lower MIC of tedizolid than of linezolid. FICIs were lowest between tedizolid and amikacin for M. abscessus (FICI = 0.75) and between tedizolid and ethambutol for M. avium (FICI = 0.72). Clarithromycin and tedizolid showed initial synergy, which was abrogated by erm(41)-induced macrolide resistance (FICI = 0.53). Tedizolid had a weak bacteriostatic effect on M. abscessus and combination with amikacin slightly prolonged its effect. Tedizolid had concentration-dependent activity against M. avium and its efficacy was enhanced by ethambutol. Both combinations had a concentration-dependent synergistic effect. Tedizolid could inhibit the intracellular bacterial population of both M. avium and M. abscessus.

Conclusions: Tedizolid should be further investigated in pharmacodynamic studies and clinical trials for M. avium complex pulmonary disease. It is less active against M. abscessus, but still promising.
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http://dx.doi.org/10.1093/jac/dkz511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021090PMC
March 2020

Economic considerations support C-reactive protein testing alongside malaria rapid diagnostic tests to guide antimicrobial therapy for patients with febrile illness in settings with low malaria endemicity.

Malar J 2019 Dec 26;18(1):442. Epub 2019 Dec 26.

Foundation of Innovative New Diagnostics (FIND), Geneva, Switzerland.

Malaria is no longer a common cause of febrile illness in many regions of the tropics. In part, this success is a result of improved access to accurate diagnosis and effective anti-malarial treatment, including in many hard-to-reach rural areas. However, in these settings, management of other causes of febrile illness remains challenging. Health systems are often weak and other than malaria rapid tests no other diagnostics are available. With millions of deaths occurring annually due to treatable bacterial infections and the ever increasing spread of antimicrobial resistance, improvement in the management of febrile illness is a global public health priority. Whilst numerous promising point-of-care diagnostics are in the pipeline, substantial progress can be made in the interim with existing tools: C-reactive protein (CRP) is a highly sensitive and moderately specific biomarker of bacterial infection and has been in clinical use for these purposes for decades, with dozens of low-cost devices commercially available. This paper takes a health-economics approach to consider the possible advantages of CRP point-of-care tests alongside rapid diagnostic tests for malaria, potentially in a single multiplex device, to guide antimicrobial therapy for patients with febrile illness. Three rudimentary assessments of the costs and benefits of this approach all indicate that this is likely to be cost-effective when considering the incremental costs of the CRP tests as compared with either (i) the improved health outcomes for patients with bacterial illnesses; (ii) the costs of antimicrobial resistance averted; or (iii) the economic benefits of better management of remaining malaria cases and shorter malaria elimination campaigns in areas of low transmission. While CRP-guided antibiotic therapy alone cannot resolve all challenges associated with management of febrile illness in remote tropical settings, in the short-term a multiplexed CRP and malaria RDT could be highly cost-effective and utilize the well-established funding and distribution systems already in place for malaria RDTs. These findings should spark further interest amongst industry, academics and policy-makers in the development and deployment of such diagnostics, and discussion on their geographically appropriate use.
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http://dx.doi.org/10.1186/s12936-019-3059-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933672PMC
December 2019

An exploration of the gut and environmental resistome in a community in northern Vietnam in relation to antibiotic use.

Antimicrob Resist Infect Control 2019 28;8:194. Epub 2019 Nov 28.

2Department of Medical Microbiology and Radboudumc Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.

Background: Antibiotic resistance is a major global public health threat. Antibiotic use can directly impact the antibiotic resistant genes (ARGs) profile of the human intestinal microbiome and consequently the environment through shedding.

Methods: We determined the resistome of human feces, animal stools, human food and environmental (rain, well, and irrigative water) samples ( = 304) in 40 households within a community cohort and related the data to antibiotic consumption. Metagenomic DNA was isolated and qPCR was used to determine presence of mobile colistin resistance () genes, genes encoding extended-spectrum β-lactamases (ESBL), carbapenemases and quinolone resistance genes.

Results: Nearly 40 % (39.5%, 120/304) of samples contained ESBL genes (most frequent were (23.7% [72/304]), (18.8% [57/304]). Quinolone resistance genes () were detected in all human and 91% (41/45) of animal stool samples. were predominantly detected in human feces at 88% (82/93) and 55% (51/93) and animal feces at 93% (42/45) and 51% (23/45), respectively. were not detected in human feces, and only sporadically (< 6%) in other samples. Carbapenemase-encoding genes were most common in water (15% [14/91]) and cooked food (13% [10/75]) samples, while their prevalence in human and animal stools was lower at 4% in both human (4/93) and animal (2/45) samples. We did not find an association between recent antibiotic consumption and ARGs in human stools. Principal component analysis showed that the resistome differs between ecosystems with a strong separation of ARGs profiles of human and animal stools on the one hand versus cooked food and water samples on the other.

Conclusions: Our study indicated that ARGs were abundant in human and animal stools in a rural Vietnamese community, including ARGs targeting last resort antibiotics. The resistomes of animal and human stools were similar as opposed to the resistomes from water and food sources. No association between antibiotic use and ARG profiles was found in a setting of high background rates of AMR.
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http://dx.doi.org/10.1186/s13756-019-0645-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883630PMC
July 2020

Development of an algorithm to discriminate between plasmid- and chromosomal-mediated AmpC β-lactamase production in Escherichia coli by elaborate phenotypic and genotypic characterization.

J Antimicrob Chemother 2019 12;74(12):3481-3488

Department of Medical Microbiology and Radboudumc Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.

Objectives: AmpC-β-lactamase production is an under-recognized antibiotic resistance mechanism that renders Gram-negative bacteria resistant to common β-lactam antibiotics, similar to the well-known ESBLs. For infection control purposes, it is important to be able to discriminate between plasmid-mediated AmpC (pAmpC) production and chromosomal-mediated AmpC (cAmpC) hyperproduction in Gram-negative bacteria as pAmpC requires isolation precautions to minimize the risk of horizontal gene transmission. Detecting pAmpC in Escherichia coli is challenging, as both pAmpC production and cAmpC hyperproduction may lead to third-generation cephalosporin resistance.

Methods: We tested a collection of E. coli strains suspected to produce AmpC. Elaborate susceptibility testing for third-generation cephalosporins, WGS and machine learning were used to develop an algorithm to determine ampC genotypes in E. coli. WGS was applied to detect pampC genes, cAmpC hyperproducers and STs.

Results: In total, 172 E. coli strains (n=75 ST) were divided into a training set and two validation sets. Ninety strains were pampC positive, the predominant gene being blaCMY-2 (86.7%), followed by blaDHA-1 (7.8%), and 59 strains were cAmpC hyperproducers. The algorithm used a cefotaxime MIC value above 6 mg/L to identify pampC-positive E. coli and an MIC value of 0.5 mg/L to discriminate between cAmpC-hyperproducing and non-cAmpC-hyperproducing E. coli strains. Accuracy was 0.88 (95% CI=0.79-0.94) on the training set, 0.79 (95% CI=0.64-0.89) on validation set 1 and 0.85 (95% CI=0.71-0.94) on validation set 2.

Conclusions: This approach resulted in a pragmatic algorithm for differentiating ampC genotypes in E. coli based on phenotypic susceptibility testing.
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http://dx.doi.org/10.1093/jac/dkz362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183348PMC
December 2019

Clinical cure rate and cost-effectiveness of carbapenem-sparing beta-lactams vs. meropenem for Gram-negative infections: A systematic review, meta-analysis, and cost-effectiveness analysis.

Int J Antimicrob Agents 2019 Dec 5;54(6):790-797. Epub 2019 Jul 5.

Department of Medical Microbiology, Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands. Electronic address:

The increasing incidence of infections caused by extended-spectrum beta-lactamase (ESBL)/AmpC-producing bacteria leads to increasing use of carbapenems and risk of carbapenem resistance. Treatment success of carbapenem-sparing beta-lactams (CSBs) for ESBL infections is unclear. The aim of this study was to appraise the clinical cure rate and estimate the cost-effectiveness of meropenem vs. CSBs (piperacillin-tazobactam, temocillin, ceftazidime-avibactam, and ceftolozane-tazobactam) for urinary tract infections (UTIs) or intra-abdominal infections (IAIs) due to ESBL/AmpC-producing bacteria. A systematic literature search of the Cochrane library, EMBASE, PubMed, and Web of Science was conducted to identify studies assessing the clinical cure rate of the antibiotics. To assess the cost-effectiveness of CSBs vs. meropenem, a combined decision analytic and Markov model was probabilistically analysed over a 5-year period. The main outcome was presented as the incremental cost-effectiveness ratio and evaluated with a threshold of €20 000 per life year gained (LYG). From 656 identified articles, 17 and 14 studies were included in the qualitative synthesis and quantitative synthesis, respectively. A clinical cure of ceftazidime-avibactam and ceftolozane-tazobactam was comparable to meropenem in patients with complicated IAIs (cIAIs) due to ESBL (Risk ratio [RR]=1·04, 95% confidence interval [CI]=0·95-1·13). Both temocillin and ceftolozane-tazobactam were deemed cost-effective compared to meropenem with €157·58 and €13 398·34 per LYG, respectively, in patients with UTIs due to ESBL. However, only ceftazidime-avibactam (plus metronidazole) was cost-effective for the treatment of IAIs, with €16 916·77 per LYG. These results show that several CSBs can be considered as viable candidates for the treatment of UTIs and IAIs caused by ESBL.
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http://dx.doi.org/10.1016/j.ijantimicag.2019.07.003DOI Listing
December 2019

Auranofin Activity Exposes Thioredoxin Reductase as a Viable Drug Target in .

Antimicrob Agents Chemother 2019 09 23;63(9). Epub 2019 Aug 23.

Radboud Center for Infectious Diseases, Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands

Nontuberculous mycobacteria (NTM) are highly drug-resistant, opportunistic pathogens that can cause pulmonary disease. The outcomes of the currently recommended treatment regimens are poor, especially for New or repurposed drugs are direly needed. Auranofin, a gold-based antirheumatic agent, was investigated for Here, we test auranofin against NTM and We tested the susceptibility of 63 NTM isolates to auranofin using broth microdilution. Next, we assessed synergy between auranofin and antimycobacterial drugs using the checkerboard method and calculated the fractional inhibition concentration index (FICI). Using time-kill kinetics assays (TK), we assessed pharmacodynamics of auranofin alone and in combination with drug combinations showing the lowest FICIs for CIP 104536. A response surface analysis was used to assess synergistic interactions over time in TKs. Primary isolated macrophages were infected with and treated with auranofin. Finally, using KEGG Orthology, we looked for orthologues to auranofins drug target in had the lowest auranofin MIC (2 μg/ml) among the tested NTM. The lowest average FICIs were observed between auranofin and amikacin (0.45) and linezolid (0.50). Auranofin exhibited concentration-dependent killing of , with >1-log killing at concentrations of >2× MIC. Only amikacin was synergistic with auranofin according to Bliss independence. Auranofin could not lower the intracellular bacterial load in macrophages. Auranofin itself may not be feasible for treatment, but these data point toward a promising, unutilized drug target.
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http://dx.doi.org/10.1128/AAC.00449-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709478PMC
September 2019

Essential and forgotten antibiotics: An inventory in low- and middle-income countries.

Int J Antimicrob Agents 2019 Sep 28;54(3):273-282. Epub 2019 Jun 28.

Université de Lorraine, APEMAC, Nancy, France; Université de Lorraine, CHRU-Nancy, Infectious Diseases Department, Nancy, France.

Background: The World Health Organization Essential Medicines List (WHO-EML) includes 'access' antibiotics, judged essential to treat common infections. The European Society of Clinical Microbiology and Infectious Diseases Study Group for Antimicrobial Stewardship defined a list of 'forgotten' antibiotics, some old and often off-patent antibiotics, which have particular value for specific indications.

Objective: To investigate which WHO-EML 'access' and 'forgotten' antibiotics are approved at national level in a sample of low- to middle-income countries (LMICs).

Methods: The Scientific Committee used a consensus procedure to select 26 WHO-EML 'access' and 15 'forgotten' antibiotics. Paediatric formulations were explored for 14 antibiotics. An internet-based questionnaire was circulated to 40 LMIC representatives. Antibiotics were defined as approved if an official drug regulatory agency and/or the national ministry of health licensed their use, making them, at least theoretically, available on the market.

Results: Twenty-eight LMICs (11 in Africa, 11 in Asia and six in America) were surveyed. Nine WHO-EML 'access' antibiotics (amoxicillin, ampicillin, benzylpenicillin, ceftriaxone, clarithromycin, ciprofloxacin, doxycycline, gentamicin and metronidazole) were approved in all countries, and all 26 'access' antibiotics were approved in more than two-thirds of countries. Among the 15 'forgotten' antibiotics, only one was approved in more than two-thirds of countries. The median number of approved antibiotics per country was 30 (interquartile range 23-35). Six of 14 paediatric formulations (amoxicillin, amoxicillin-clavulanic acid, oral antistaphylococcal penicillin, cotrimoxazole, erythromycin and metronidazole) were approved in more than two-thirds of countries.

Conclusions: WHO-EML 'access' antibiotics and the most frequently used formulations for paediatrics were approved in the vast majority of the 28 surveyed LMICs. This was not the case for many of the 'forgotten' antibiotics, despite their important role, particularly in areas with high prevalence of multi-drug-resistant bacteria.
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http://dx.doi.org/10.1016/j.ijantimicag.2019.06.017DOI Listing
September 2019

Antimicrobial susceptibility testing and antibiotic consumption results from 16 hospitals in Viet Nam: The VINARES project 2012-2013.

J Glob Antimicrob Resist 2019 09 12;18:269-278. Epub 2019 Jun 12.

Oxford University Clinical Research Unit, Viet Nam; Department of Medical Microbiology and Radboudumc Center for Infectious Diseases, Radboudumc, Nijmegen, Netherlands.

Objective: To establish a hospital-based surveillance network with national coverage for antimicrobial resistance (AMR) and antibiotic consumption in Viet Nam.

Methods: A 16-hospital network (Viet Nam Resistance: VINARES) was established and consisted of national and provincial-level hospitals across the country. Antimicrobial susceptibility testing results from routine clinical diagnostic specimens and antibiotic consumption data in Defined Daily Dose per 1000 bed days (DDD/1000 patient-days) were prospectively collected and analysed between October 2012 and September 2013.

Results: Data from a total of 24 732 de-duplicated clinical isolates were reported. The most common bacteria were: Escherichia coli (4437 isolates, 18%), Klebsiella spp. (3290 isolates, 13%) and Acinetobacter spp. (2895 isolates, 12%). The hospital average antibiotic consumption was 918 DDD/1000 patient-days. Third-generation cephalosporins were the most frequently used antibiotic class (223 DDD/1000 patient-days, 24%), followed by fluoroquinolones (151 DDD/1000 patient-days, 16%) and second-generation cephalosporins (112 DDD/1000 patient-days, 12%). Proportions of antibiotic resistance were high: 1098/1580 (69%) Staphylococcus aureus isolates were methicillin-resistant (MRSA); 115/344 isolates (33%) and 90/358 (25%) Streptococcus pneumoniae had reduced susceptibility to penicillin and ceftriaxone, respectively. A total of 180/2977 (6%) E. coli and 242/1526 (16%) Klebsiella pneumoniae were resistant to imipenem, respectively; 602/1826 (33%) Pseudomonas aeruginosa were resistant to ceftazidime and 578/1765 (33%) to imipenem. Of Acinetobacter spp. 1495/2138 (70%) were resistant to carbapenems and 2/333 (1%) to colistin.

Conclusions: These data are valuable in providing a baseline for AMR among common bacterial pathogens in Vietnamese hospitals and to assess the impact of interventions.
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http://dx.doi.org/10.1016/j.jgar.2019.06.002DOI Listing
September 2019

Evaluation of Prolonged vs Short Courses of Antibiotic Prophylaxis Following Ear, Nose, Throat, and Oral and Maxillofacial Surgery: A Systematic Review and Meta-analysis.

JAMA Otolaryngol Head Neck Surg 2019 07;145(7):610-616

Division of Medical Microbiology and Radboudumc Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.

Importance: Antibiotic prophylaxis is widely used after surgical procedures operating on the mucosal tissues of the aerodigestive tract, but the optimal duration of these prophylactic therapies is often unclear.

Objective: To compare short-course antibiotic prophylaxis (≤24 hours) vs extended-course antibiotic prophylaxis (≥72 hours) after ear, nose, throat, and oral and maxillofacial surgery.

Data Sources And Study Selection: Literature searches of PubMed were completed in October 2017 and included prospective trials that compared antibiotic prophylaxis courses of 24 hours or less vs 72 hours or more after ear, nose, throat, and oral and maxillofacial surgery. Some studies were also handpicked from reference lists of studies found with the initial search terms. All analysis was performed between September 2017 and October 2018.

Data Extraction And Synthesis: All review stages were conducted in consensus by 2 reviewers. Data extraction and study quality assessment were performed with the Cochrane data extraction form and the Cochrane risk of bias tool. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used for reporting. The fixed-effects Mantel-Haenszel method was used for meta-analysis.

Main Outcomes And Measures: Relative risk (RR) of surgical site infections, microbial origins of surgical site infections, adverse events, duration of hospital stay, and treatment costs.

Results: Included in the meta-analysis were 21 articles with a cumulative 1974 patients. In patients receiving 24 hours or shorter vs 72 hours or longer antibiotic prophylaxis regimens, no significant difference was found in the occurrence of postoperative infections in the pooled population (RR, 0.90; 95% CI, 0.67-1.19), or in the ear, nose, throat (RR, 0.89; 95% CI, 0.54-1.45), and oral and maxillofacial populations (RR, 0.88; 95% CI, 0.63-1.21), separately. No heterogeneity was observed overall or in the subgroups. Patients receiving extended-course antibiotic prophylaxis were significantly more likely to develop adverse events unrelated to the surgical site (RR, 2.40; 95% CI, 1.20-3.54).

Conclusions And Relevance: No difference was found in the occurrence of postoperative infections between short-course and extended-course antibiotic prophylaxis after ear, nose, throat, and oral and maxillofacial surgery. Therefore, a short course of antibiotic prophylaxis is recommended unless documented conditions are present that would be best treated with an extended course. Using short-course antibiotics could avoid additional adverse events, antibiotic resistance development, and higher hospital costs. Future research should focus on identifying risk groups that might benefit from prolonged prophylaxis.
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http://dx.doi.org/10.1001/jamaoto.2019.0879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512286PMC
July 2019

Minocycline treatment for pulmonary Mycobacterium avium complex disease based on pharmacokinetics/pharmacodynamics and Bayesian framework mathematical models.

J Antimicrob Chemother 2019 07;74(7):1952-1961

Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA.

Objectives: Our aim was to identify the pharmacokinetic/pharmacodynamic parameters of minocycline in the hollow-fibre system (HFS) model of pulmonary Mycobacterium avium complex (MAC) and to identify the optimal clinical dose.

Methods: Minocycline MICs for 55 MAC clinical isolates from the Netherlands were determined. We also co-incubated primary isolated macrophages infected with MAC with minocycline. Next, we performed a 28 day HFS-MAC model dose-response study in which we mimicked pulmonary concentration-time profiles achieved in patients. The HFS-MAC model was sampled at intervals to determine the minocycline pharmacokinetics and MAC burden. We identified the AUC0-24/MIC ratios associated with 1.0 log10 cfu/mL kill below day 0 (stasis), defined as a bactericidal effect. We then performed 10000 Monte Carlo experiments to identify the optimal dose for a bactericidal effect in patients.

Results: The MIC for 50% and 90% of cumulative clinical isolates was 8 and 64 mg/L, respectively. Minocycline decreased MAC bacterial burden below stasis in primary isolated macrophages. In the HFS-MAC model, minocycline achieved a microbial kill of 3.6 log10 cfu/mL below stasis. The AUC0-24/MIC exposure associated with a bactericidal effect was 59. Monte Carlo experiments identified a minocycline susceptibility MIC breakpoint of 16 mg/L. At this proposed breakpoint, the clinical dose of 200 mg/day achieved the bactericidal effect exposure target in ∼50% of patients, while 400 mg/day achieved this in 73.6% of patients, in Monte Carlo experiments.

Conclusions: Minocycline at a dose of 400 mg/day is expected to be bactericidal. We propose a clinical trial for validation.
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http://dx.doi.org/10.1093/jac/dkz143DOI Listing
July 2019

A randomised controlled trial of matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDITOF-MS) versus conventional microbiological methods for identifying pathogens: Impact on optimal antimicrobial therapy of invasive bacterial and fungal infections in Vietnam.

J Infect 2019 06 23;78(6):454-460. Epub 2019 Mar 23.

Centre for Tropical Medicine & Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom; Department of Medical Microbiology, RadboudUMC, Nijmegen, The Netherlands.

Objectives: We assessed the impact of MALDITOF-MS on the timeliness of optimal antimicrobial therapy through a parallel-arm randomised controlled trial in two hospitals in Vietnam.

Methods: We recruited patients with a pathogen (bacterial or fungal) cultured from a normally sterile sample. Samples were randomly assigned (1:1) to identification by MALDITOF-MS or conventional diagnostics. The primary outcome was the proportion on optimal antimicrobial therapy within 24 h of positive culture, determined by a blinded independent review committee. Trial registered at ClinicalTrials.gov (NCT02306330).

Results: Among 1005 randomised patients, pathogens were isolated from 628 (326 intervention, 302 control), with 377 excluded as likely contaminants or discharged/died before positive culture. Most isolates were cultured from blood (421/628, 67.0%). The proportion receiving optimal antimicrobial therapy within 24 h (the primary outcome) or 48 h of growth was not significantly different between MALDITOF-MS and control arms (135/326, 41.4% vs 120/302, 39.7%; Adjusted Odds ration (AOR) 1.17, p = 0.40 and 151/326, 46.3% vs 141/302, 46.7%; AOR 1.05 p = 0.79, respectively).

Conclusions: MALDITOF-MS, in the absence of an antimicrobial stewardship programme, did not improve the proportion on optimal antimicrobial therapy at 24 or 48 h after first growth in a lower-middle income setting with high rates of antibiotic resistance.
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http://dx.doi.org/10.1016/j.jinf.2019.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529875PMC
June 2019

Sero-Prevalence Surveillance to Predict Vaccine-Preventable Disease Outbreaks; A Lesson from the 2014 Measles Epidemic in Northern Vietnam.

Open Forum Infect Dis 2019 Mar 24;6(3):ofz030. Epub 2019 Jan 24.

Oxford University Clinical Research Unit, Wellcome Trust Asia Programme, Hanoi, Vietnam.

Background: During the first half of 2014, a severe outbreak of measles occurred in northern Vietnam, causing 15 033 confirmed cases and 146 deaths.

Methods: To evaluate the population-level seroprevalence of protection against measles in the period before the outbreak, we made use of an existing age-stratified serum bank, collected over the year before the outbreak, between November 2012 and December 2013, from 4 sites across the country (Hanoi, Hue, Dak Lak, and Ho Chi Minh City). Data from the UNICEF's Multiple Indicator Clustered Surveys (MICS), carried out in Vietnam during the first quarter of 2014, were used to assess the vaccine coverage in 6 ecological regions of Vietnam.

Results: Results revealed a large discrepancy between levels of protection, as estimated from the serology and vaccine coverage estimated by UNICEF's MICS. Variation in seroprevalence across locations and age groups corresponded with reported numbers of measles cases, most of which were among the 0-2-year-old age group and in the northern part of the country.

Conclusions: Our study presents a strong case in favor of a serosurveillance sentinel network that could be used to proactively tune vaccination policies and other public health interventions.
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http://dx.doi.org/10.1093/ofid/ofz030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405937PMC
March 2019

Active contact tracing beyond the household in multidrug resistant tuberculosis in Vietnam: a cohort study.

BMC Public Health 2019 Feb 28;19(1):241. Epub 2019 Feb 28.

Oxford University Clinical Research Unit, Hanoi, Vietnam.

Background: Currently in Vietnam contact tracing for multidrug-resistant tuberculosis (MDR-TB) entails passive case finding among symptomatic household contacts who present themselves for diagnosis. Close contacts of MDR-TB cases are therefore not identified adequately. We assessed the added value of active contact tracing within and beyond households using social network questionnaires to identify close contacts of MDR-TB patients in Vietnam.

Methods: We conducted a cohort study using social network questionnaires in which contacts were identified by MDR-TB patients, including contacts from 'high risk' places like work. Contacts of MDR-TB patients were followed up and screened over a period of at least 6 months. This included two active screenings and any unscheduled passive screening of self-referred contacts during the study period.

Results: Four hundred seventeen contacts of 99 index cases were recruited, 325 (77.9%) and 160/417 (38.4%) contacts participated in the first and second screenings, respectively. The first screening detected one TB case but the bacteria were not MDR. From passive screening, a household contact was diagnosed with TB meningitis but not through our active approach. Social network analysis showed that only 1/17 (5.9%) high-risk places agreed to cooperate and were included in the screening, and no MDR-TB cases were detected. There were two pairs of index cases (identified separately) who were found to be contacts of each other and who had been diagnosed before the study started.

Conclusions: No new MDR-TB cases were detected using social network analysis of nearly 100 MDR-TB index cases, likely due to a relatively short follow up time, and loss to follow up (lack of cooperation from contacts or high risk places and lack of available resources in the National Tuberculosis Control Programme).
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http://dx.doi.org/10.1186/s12889-019-6573-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394002PMC
February 2019

Burden of disease and economic impact of human Streptococcus suis infection in Viet Nam.

Trans R Soc Trop Med Hyg 2019 06;113(6):341-350

Radboud UMC, Geert Grooteplein Zuid 10, GA, Nijmegen, the Netherlands.

Background: Streptococcus suis is a zoonotic disease mainly affecting men of working age and can result in death or long-term sequelae, including severe hearing loss and vestibular dysfunction. We aimed to quantify the burden of disease and economic impact of this infection in Viet Nam.

Methods: The annual disease incidence for the period 2011-2014 was estimated based on surveillance data using a multiple imputation approach. We calculated disease burden in disability-adjusted life years (DALYs) and economic costs using an incidence-based approach from a patient's perspective and including direct and indirect impacts of S. suis infection and its long-term sequelae.

Results: The estimated annual incidence rate was 0.318, 0.324, 0.255 and 0.249 cases per 100 000 population in 2011, 2012, 2013 and 2014, respectively. The corresponding DALYs lost were 1832, 1866, 1467 and 1437. The mean direct cost per episode was US$1635 (95% confidence interval 1352-1923). The annual direct cost was US$370 000-500 000 and the indirect cost was US$2.27-2.88 million in this time period.

Conclusions: This study showed a large disease burden and high economic impact of S. suis infection and provides important data for disease monitoring and control.
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http://dx.doi.org/10.1093/trstmh/trz004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580695PMC
June 2019