Cost Effectiveness of Rectal Culture-based Antibiotic Prophylaxis in Transrectal Prostate Biopsy: The Results from a Randomized, Nonblinded, Multicenter Trial.

Background: Culture-based antibiotic prophylaxis is a plausible strategy to reduce infections after transrectal prostate biopsy (PB) related to fluoroquinolone-resistant pathogens. Objective: To assess the cost effectiveness of rectal culture-based prophylaxis compared with empirical ciprofloxacin prophylaxis. Design setting and participants: The study was performed alongside a trial in 11 Dutch hospitals investigating the effectiveness of culture-based prophylaxis in transrectal PB between April 2018 and July 2021 (trial registration number: NCT03228108). Intervention: Patients were 1:1 randomized for empirical ciprofloxacin prophylaxis (oral) or culture-based prophylaxis. Costs for both prophylactic strategies were determined for two scenarios: (1) all infectious complications within 7 d after biopsy and (2) culture-proven Gram-negative infections within 30 d after biopsy. Outcome measurements and statistical analysis: Differences in costs and effects (quality-adjusted life-years [QALYs]) were analyzed from a healthcare and societal perspective (including productivity losses, and travel and parking costs) using a bootstrap procedure presenting uncertainty surrounding the incremental cost-effectiveness ratio in a cost-effectiveness plane and acceptability curve. Results and limitations: For the 7-d follow-up period, culture-based prophylaxis (n = 636) was €51.57 (95% confidence interval [CI] 6.52-96.63) more expensive from a healthcare perspective and €16.95 (95% CI -54.29 to 88.18) from a societal perspective than empirical ciprofloxacin prophylaxis (n = 652). Ciprofloxacin-resistant bacteria were detected in 15.4%. Extrapolating our data, from a healthcare perspective, 40% ciprofloxacin resistance would lead to equal cost for both strategies. Results were similar for the 30-d follow-up period. No significant differences in QALYs were observed. Conclusions: Our results should be interpreted in the context of local ciprofloxacin resistance rates. In our setting, from a healthcare perspective, culture-based prophylaxis was significantly more expensive than empirical ciprofloxacin prophylaxis. From a societal perspective, culture-based prophylaxis was somewhat more cost effective against the threshold value customary for the Netherlands (€80.000). Patient summary: Culture-based prophylaxis in transrectal prostate biopsy was not associated with reduced costs compared with empirical ciprofloxacin prophylaxis.

Moderate and transient impact of antibiotic use on the gut microbiota in a rural Vietnamese cohort.

The human gut microbiota has been shown to be significantly perturbed by antibiotic use, while recovering to the pre-treatment state several weeks after short antibiotic exposure. The effects of antibiotics on the gut microbiota have however been mainly documented in high-income settings with lower levels of antibiotic resistance as compared to lower and middle income countries (LMIC). This study aimed to examine the long-term consequences of repeated exposure to commonly use antibiotics on the fecal microbiota of residents living in a low income setting with high prevalence of antibiotic resistance. Fecal samples from household individuals (n = 63) participating in a rural cohort in northern Vietnam were collected monthly for a period of 6 months. Using 16S V4 rRNA gene region amplicon sequencing and linear mixed-effects models analysis, we observed only a minor and transient effect of antibiotics on the microbial richness (ß = - 31.3, 95%CI = - 55.3, - 7.3, p = 0.011), while the microbial diversity was even less affected (ß = - 0.298, 95%CI - 0.686, 0.090, p = 0.132). Principal Component Analyses (PCA) did not reveal separation of samples into distinct microbiota-based clusters by antibiotics use, suggesting the microbiota composition was not affected by the antibiotics commonly used in this population. Additionally, the fecal microbial diversity of the subjects in our study cohort was lower when compared to that of healthy Dutch adults (median 3.95 (IQR 3.72-4.13) vs median 3.69 (IQR3.31-4.11), p = 0.028, despite the higher dietary fiber content in the Vietnamese as compared to western diet. Our findings support the hypothesis that frequent antibiotic exposure may push the microbiota to a different steady state that is less diverse but more resilient to disruption by subsequent antibiotic use.

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

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.

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.

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.

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.

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.

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

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.

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

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.

Risk Assessment After a Severe Hospital-Acquired Infection Associated With Carbapenemase-Producing Pseudomonas aeruginosa.

Importance: Resistance of gram-negative bacilli to carbapenems is rapidly emerging worldwide. In 2016, the World Health Organization defined the hospital-built environment as a core component of infection prevention and control programs. The hospital-built environment has recently been reported as a source for outbreaks and sporadic transmission events of carbapenemase-producing gram-negative bacilli from the environment to patients. Objective: To assess risk after the identification of an unexpected, severe, and lethal hospital-acquired infection caused by carbapenemase-producing Pseudomonas aeruginosa in a carbapenemase-low endemic setting. Design, Settings, and Participants: A case series study in which a risk assessment was performed on all 11 patients admitted to the combined cardiothoracic surgery and pulmonary diseases ward and the hospital-built environment in the Radboud University Medical Center, the Netherlands, in February 2018. Exposures: Water and aerosols containing carbapenemase-producing (Verona integron-mediated metallo-ß-lactamase [VIM]) P aeruginosa. Main Outcomes and Measures: Colonization and/or infection of patients and/or contamination of the environment after the detection of 1 patient infected with carbapenemase-producing (VIM) P aeruginosa. Results: A total of 5 men (age range, 60-84 years) and 6 women (age range, 55-74 years) were admitted to the combined cardiothoracic surgery and pulmonary diseases ward. The risk assessment was performed after carbapenemase-producing (VIM) P aeruginosa was unexpectedly detected in a man in his early 60s, who had undergone a left-sided pneumonectomy and adjuvant radiotherapy. No additional cases (colonization or infection) of carbapenemase-producing (VIM) P aeruginosa were detected. Plausible transmission of carbapenemase-producing P aeruginosa from the hospital environment to the patient via the air was confirmed by whole-genome sequencing, which proved the relation of Pseudomonas strains from the patient, the shower drains in 8 patient rooms, 1 sink, and an air sample. Conclusions and Relevance: This study suggests that rethinking the hospital-built environment, including shower drains and the sewage system, will be crucial for the prevention of severe and potential lethal hospital-acquired infections.

C-reactive protein point of care testing in the management of acute respiratory infections in the Vietnamese primary healthcare setting - a cost benefit analysis.

Aim: We assess the cost-benefit implications of C-reactive protein (CRP) testing in reducing antibiotic prescription for acute respiratory infection in Viet Nam by comparing the incremental costs of CRP testing with the economic costs of antimicrobial resistance averted due to lower antibiotic prescribing. Findings: Patients in the CRP group and the controls incurred similar costs in managing their illness, excluding the costs of the quantitative CRP tests, provided free of charge in the trial context. Assuming a unit cost of $1 per test, the incremental cost of CRP testing was $0.93 per patient. Based on a previous modelling analysis, the 20 percentage point reduction in prescribing observed in the trial implies a societal benefit of $0.82 per patient. With the low levels of adherence to the test results observed in the trial, CRP testing would not be cost-beneficial. The sensitivity analyses showed, however, that with higher adherence to test results their use would be cost-beneficial.

Cost-effectiveness of a hand hygiene program on health care-associated infections in intensive care patients at a tertiary care hospital in Vietnam.

BACKGROUND: The cost-effectiveness of a hand hygiene (HH) program in low- and middle-income countries (LMICs) is largely unknown. We assessed the cost-effectiveness of a HH program in a large tertiary Vietnamese hospital. METHODS: This was a before and after study of a hand hygiene program where HH compliance, incidence of hospital-acquired infections (HAIs), and costs were analyzed.The HH program was implemented in 2 intensive care and 15 critical care units. The program included upgrading HH facilities, providing alcohol-based handrub at point of care, HH campaigns, and continuous HH education. RESULTS: The HH compliance rate increased from 25.7% to 57.5% (P < .001). The incidence of patients with HAI decreased from 31.7% to 20.3% (P < .001) after the intervention. The mean cost for patients with HAI was $1,908, which was 2.5 times higher than the costs for patients without an HAI. The mean attributable cost of an HAI was $1,131. The total cost of the HH program was $12,570, which equates to a per-patient cost of $6.5. The cost-effectiveness was estimated at -$1,074 or $1,074 saved per HAI prevented. The intervention remained cost savings under various scenarios with lower HAI rates. CONCLUSION: The HH program is an effective strategy in reducing the incidence of HAIs in intensive care units and is cost-effective in Vietnam. HH programs need to be encouraged across Vietnam and other LMICs.

Antibiotic use and resistance in emerging economies: a situation analysis for Viet Nam.

BACKGROUND: Antimicrobial resistance is a major contemporary public health threat. Strategies to contain antimicrobial resistance have been comprehensively set forth, however in developing countries where the need for effective antimicrobials is greatest implementation has proved problematic. A better understanding of patterns and determinants of antibiotic use and resistance in emerging economies may permit more appropriately targeted interventions.Viet Nam, with a large population, high burden of infectious disease and relatively unrestricted access to medication, is an excellent case study of the difficulties faced by emerging economies in controlling antimicrobial resistance. METHODS: Our working group conducted a situation analysis of the current patterns and determinants of antibiotic use and resistance in Viet Nam. International publications and local reports published between 1-1-1990 and 31-8-2012 were reviewed. All stakeholders analyzed the findings at a policy workshop and feasible recommendations were suggested to improve antibiotic use in Viet Nam.Here we report the results of our situation analysis focusing on: the healthcare system, drug regulation and supply; antibiotic resistance and infection control; and agricultural antibiotic use. RESULTS: Market reforms have improved healthcare access in Viet Nam and contributed to better health outcomes. However, increased accessibility has been accompanied by injudicious antibiotic use in hospitals and the community, with predictable escalation in bacterial resistance. Prescribing practices are poor and self-medication is common - often being the most affordable way to access healthcare. Many policies exist to regulate antibiotic use but enforcement is insufficient or lacking.Pneumococcal penicillin-resistance rates are the highest in Asia and carbapenem-resistant bacteria (notably NDM-1) have recently emerged. Hospital acquired infections, predominantly with multi-drug resistant Gram-negative organisms, place additional strain on limited resources. Widespread agricultural antibiotic use further propagates antimicrobial resistance. CONCLUSIONS: Future legislation regarding antibiotic access must alter incentives for purchasers and providers and ensure effective enforcement. The Ministry of Health recently initiated a national action plan and approved a multicenter health improvement project to strengthen national capacity for antimicrobial stewardship in Viet Nam. This analysis provided important input to these initiatives. Our methodologies and findings may be of use to others across the world tackling the growing threat of antibiotic resistance.

Antibiotic resistance-the need for global solutions.

The causes of antibiotic resistance are complex and include human behaviour at many levels of society; the consequences affect everybody in the world. Similarities with climate change are evident. Many efforts have been made to describe the many different facets of antibiotic resistance and the interventions needed to meet the challenge. However, coordinated action is largely absent, especially at the political level, both nationally and internationally. Antibiotics paved the way for unprecedented medical and societal developments, and are today indispensible in all health systems. Achievements in modern medicine, such as major surgery, organ transplantation, treatment of preterm babies, and cancer chemotherapy, which we today take for granted, would not be possible without access to effective treatment for bacterial infections. Within just a few years, we might be faced with dire setbacks, medically, socially, and economically, unless real and unprecedented global coordinated actions are immediately taken. Here, we describe the global situation of antibiotic resistance, its major causes and consequences, and identify key areas in which action is urgently needed.

Studying the effectiveness of activated carbon R95 respirators in reducing the inhalation of combustion by-products in Hanoi, Vietnam: a demonstration study.

BACKGROUND: Urban air pollution is an increasing health problem, particularly in Asia, where the combustion of fossil fuels has increased rapidly as a result of industrialization and socio-economic development. The adverse health impacts of urban air pollution are well established, but less is known about effective intervention strategies. In this demonstration study we set out to establish methods to assess whether wearing an R95 activated carbon respirator could reduce intake of polycyclic aromatic hydrocarbons (PAH) in street workers in Hanoi, Vietnam. METHODS: In this demonstration study we performed a cross-over study in which non-smoking participants that worked at least 4 hours per day on the street in Hanoi were randomly allocated to specific respirator wearing sequences for a duration of 2 weeks. Urines were collected after each period, i.e., twice per week, at the end of the working day to measure hydroxy PAHs (OH-PAH) using gas chromatography/high resolution mass spectrometry. The primary endpoint was the urinary concentration of 1-hydroxypyrene (1-OHP). RESULTS: Forty-four participants (54.5% male, median age 40 years) were enrolled with the majority being motorbike taxi drivers (38.6%) or street vendors (34.1%). The baseline creatinine corrected urinary level for 1-OHP was much higher than other international comparisons: 1020 ng/g creatinine (IQR: 604-1551). Wearing a R95 mask had no significant effect on 1-OHP levels: estimated multiplicative effect 1.0 (95% CI: 0.92-1.09) or other OH-PAHs, except 1-hydroxynaphthalene (1-OHN): 0.86 (95% CI: 0.11-0.96). CONCLUSIONS: High levels of urine OH-PAHs were found in Hanoi street workers. No effect was seen on urine OH-PAH levels by wearing R95 particulate respirators in an area of high urban air pollution, except for 1-OHN. A lack of effect may be de to gaseous phase PAHs that were not filtered efficiently by the respirator. The high levels of urinary OH-PAHs found, urges for effective interventions. TRIAL REGISTRATION: ISRCTN74390617 (date of assignation: 04/08/2009).