Summary Background Antibiotic drug consumption is a major driver of antibiotic resistance. Variations in antibiotic resistance across countries are attributable, in part, to different volumes and patterns for antibiotic consumption. We aimed to assess variations in consumption to assist monitoring of the rise of resistance and development of rational-use policies and to provide a baseline for future assessment. Methods With use of sales data for retail and hospital pharmacies from the IMS Health MIDAS database, we reviewed trends for consumption of standard units of antibiotics between 2000 and 2010 for 71 countries. We used compound annual growth rates to assess temporal differences in consumption for each country and Fourier series and regression methods to assess seasonal differences in consumption in 63 of the countries. Findings Between 2000 and 2010, consumption of antibiotic drugs increased by 35% (from 52 057 163 835 standard units to 70 440 786 553). Brazil, Russia, India, China, and South Africa accounted for 76% of this increase. In most countries, antibiotic consumption varied significantly with season. There was increased consumption of carbapenems (45%) and polymixins (13%), two last-resort classes of antibiotic drugs. Interpretation The rise of antibiotic consumption and the increase in use of last-resort antibiotic drugs raises serious concerns for public health. Appropriate use of antibiotics in developing countries should be encouraged. However, to prevent a striking rise in resistance in low-income and middle-income countries with large populations and to preserve antibiotic efficacy worldwide, programmes that promote rational use through coordinated efforts by the international community should be a priority. Funding US Department of Homeland Security, Bill & Melinda Gates Foundation, US National Institutes of Health, Princeton Grand Challenges Program.

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Global antibiotic consumption 2000 to 2010: an analysis of national pharmaceutical sales data

Infections caused by antibiotic-resistant bacteria, especially the “ESKAPE” pathogens, continue to increase in frequency and cause significant morbidity and mortality. New antimicrobial agents are greatly needed to treat infections caused by gram-negative bacilli (GNB) resistant to currently available agents. The Infectious Diseases Society of America (IDSA) continues to propose legislative, regulatory, and funding solutions to this continuing crisis. The current report updates the status of development and approval of systemic antibiotics in the United States as of early 2013. Only 2 new antibiotics have been approved since IDSA's 2009 pipeline status report, and the number of new antibiotics annually approved for marketing in the United States continues to decline. We identified 7 drugs in clinical development for treatment of infections caused by resistant GNB. None of these agents was included in our 2009 list of antibacterial compounds in phase 2 or later development, but unfortunately none addresses the entire spectrum of clinically relevant GNB resistance. Our survey demonstrates some progress in development of new antibacterial drugs that target infections caused by resistant GNB, but progress remains alarmingly elusive. IDSA stresses our conviction that the antibiotic pipeline problem can be solved by the collaboration of global leaders to develop creative incentives that will stimulate new antibacterial research and development. Our aim is the creation of a sustainable global antibacterial drug research and development enterprise with the power in the short term to develop 10 new, safe, and efficacious systemically administered antibiotics by 2020 as called for in IDSA's “10 × '20 Initiative.”

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10 × '20 Progress—Development of New Drugs Active Against Gram-Negative Bacilli: An Update From the Infectious Diseases Society of America

Infections caused by resistant gram-negative bacteria are becoming increasingly prevalent and now constitute a serious threat to public health worldwide because they are difficult to treat and are associated with high morbidity and mortality rates. In the United States, there has been a steady increase since 2000 in rates of extended-spectrum β-lactamase-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and multidrug-resistant strains of Pseudomonas aeruginosa and Acinetobacter baumannii, particularly among hospitalized patients with intraabdominal infections, urinary tract infections, ventilator-associated pneumonia, and bacteremia. Colonization with resistant gram-negative bacteria is common among residents in long-term care facilities (particularly those residents with an indwelling device), and these facilities are considered important originating sources of such strains for hospitals. Antibiotic resistance is associated with a substantial clinical and economic burden, including increased mortality, greater hospital and antibiotic costs, and longer stays in hospitals and intensive care units. Control of resistant gram-negative infections requires a comprehensive approach, including strategies for risk factor identification, detection and identification of resistant organisms, and implementation of infection-control and prevention strategies. In treating resistant gram-negative infections, a review of surveillance data and hospital-specific antibiograms, including resistance patterns within local institutions, and consideration of patient characteristics are helpful in guiding the choice of empiric therapy. Although only a few agents are available with activity against resistant gram-negative organisms, two recently released β-lactam/β-lactamase inhibitor combinations - ceftolozane/tazobactam and ceftazidime/avibactam - have promising activity against these organisms. In this article, we review the epidemiology, risk factors, and antibiotic resistance mechanisms of gram-negative organisms. In addition, an overview of treatment options for patients with these infections is provided.

https://accpjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/phar.1636

Infections Caused by Resistant Gram-Negative Bacteria: Epidemiology and Management

Large conjugative plasmids are important drivers of bacterial evolution and contribute significantly to the dissemination of antibiotic resistance. Although plasmid borne multidrug resistance is recognized as one of the main challenges in modern medicine, the adaptive forces shaping the evolution of these plasmids within pathogenic hosts are poorly understood. Here we study plasmid-host adaptations following transfer of a 73 kb conjugative multidrug resistance plasmid to naive clinical isolates of Klebsiella pneumoniae and Escherichia coli. We use experimental evolution, mathematical modelling and population sequencing to show that the long-term persistence and molecular integrity of the plasmid is highly influenced by multiple factors within a 25 kb plasmid region constituting a host-dependent burden. In the E. coli hosts investigated here, improved plasmid stability readily evolves via IS26 mediated deletions of costly regions from the plasmid backbone, effectively expanding the host-range of the plasmid. Although these adaptations were also beneficial to plasmid persistence in a naive K. pneumoniae host, they were never observed in this species, indicating that differential evolvability can limit opportunities of plasmid adaptation. While insertion sequences are well known to supply plasmids with adaptive traits, our findings suggest that they also play an important role in plasmid evolution by maintaining the plasticity necessary to alleviate plasmid-host constrains. Further, the observed evolutionary strategy consistently followed by all evolved E. coli lineages exposes a trade-off between horizontal and vertical transmission that may ultimately limit the dissemination potential of clinical multidrug resistance plasmids in these hosts.

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Survival and Evolution of a Large Multidrug Resistance Plasmid in New Clinical Bacterial Hosts

Bacterial resistance to conventional antibiotics has become a clinical and public health problem, making therapeutic decisions more challenging Plant compounds and nanodrugs have been proposed as potential antimicrobial alternatives Studies have shown that oregano (Origanum vulgare) essential oil (OEO) and silver nanoparticles have potent antibacterial activity, also against multidrug-resistant strains; however, the strong organoleptic characteristics of OEO and the development of resistance to these metal nanoparticles can limit their use This study evaluated the antibacterial effect of a two-drug combination of biologically synthesized silver nanoparticles (bio-AgNP), produced by Fusarium oxysporum, and OEO against Gram-positive and Gram-negative bacteria, including multidrug-resistant strains OEO and bio-AgNP showed bactericidal effects against all 17 strains tested, with minimal inhibitory concentrations (MIC) ranging from 0298 to 1193 mg/mL and 625 to 250 μM, respectively Time-kill curves indicated that OEO acted rapidly (within 10 min), while the metallic nanoparticles took 4 h to kill Gram-negative bacteria and 24 h to kill Gram-positive bacteria The combination of the two compounds resulted in a synergistic or additive effect, reducing their MIC values and reducing the time of action compared to bio-AgNP used alone, ie, 20 min for Gram-negative bacteria and 7 h for Gram-positive bacteria Scanning electron microscopy (SEM) revealed similar morphological alterations in Staphylococcus aureus (non-methicillin-resistant S aureus, non-MRSA) cells exposed to three different treatments (OEO, bio-AgNP and combination of the two), which appeared cell surface blebbing Individual and combined treatments showed reduction in cell density and decrease in exopolysaccharide matrix compared to untreated bacterial cells It indicated that this composition have an antimicrobial activity against S aureus by disrupting cells Both compounds showed very low hemolytic activity, especially at MIC levels This study describes for the first time the synergistic and additive interaction between OEO and bio-AgNP produced by F oxysporum against multidrug-resistant bacteria, such as MRSA, and β-lactamase- and carbapenemase-producing Escherichia coli and Acinetobacter baumannii strains These results indicated that this combination can be an alternative in the control of infections with few or no treatment options

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Synergistic and Additive Effect of Oregano Essential Oil and Biological Silver Nanoparticles against Multidrug-Resistant Bacterial Strains.

Extended spectrum β-lactamases (ESBLs) are enzymes produced by a variety of Gram negative bacteria which confer an increased resistance to commonly used antibiotics. They are a worrying global public health issue as infections caused by such enzyme-producing organisms are associated with a higher morbidity and mortality and greater fiscal burden. Coupled with increasing prevalence rates worldwide and an ever diminishing supply in the antibiotic armamentarium, these enzymes represent a clear and present danger to public health. This article aims to give an overview of the current situation regarding ESBLs, with a focus on the epidemiology and management of such infections.

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ESBLs: A Clear and Present Danger?

Fungal infections in the critically ill

Background: Serological testing is used to quantify SARS-CoV-2 seroprevalence, guide booster vaccination and select patients for anti-SARS-CoV-2 antibodies therapy. However, our understanding of how serological tests perform as time passes after infection is limited. Methods: Four assays were compared in parallel: 1) the multiplexed spike, nucleoprotein and receptor binding domain Meso Scale Discovery (MSD) assay 2) the Roche Elecsys-Nucleoprotein assay (Roche-N) 3) the Roche Spike assay (Roche-S) and 4) the Abbott Nucleoprotein assay (Abbott-N) on serial positive monthly samples from hospital staff up to 200 days following infection as part of the Co-Stars study. Results: We demonstrate that 50% of the Abbott-N assays give a negative result after 175 days (median survival time 95% CI 168–185 days) while the Roche-N assay (93% survival probability at 200 days, 95% CI 88–97%) maintained seropositivity. The MSD spike (97% survival probability at 200 days, 95% CI 95–99%) and the Roche-S assay (95% survival probability at 200 days, 95% CI 93–97%) also remained seropositive. The best performing quantitative Roche-S assay showed no evidence of waning Spike antibody titres over 200-days. Conclusions: The Abbott-N assay fails to detect SARS-CoV-2 antibodies as time passes since infection. In contrast the Roche and the MSD assays maintained high sensitivity. The limitations of the Abbott assay must be considered in clinical decision making. The long duration of detectable neutralizing spike antibody titres by the quantitative Roche-S assay provides further evidence in support of long-lasting SARS-CoV-2 protection to pre-existing strains of SARS-CoV-2 following natural infection.

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The Influence of Time on the Sensitivity of SARS-CoV-2 Serological Testing

Abstract Sensitive serological testing is essential to estimate the proportion of the population exposed or infected with SARS-CoV-2, to guide booster vaccination and to select patients for treatment with anti-SARS-CoV-2 antibodies. The performance of serological tests is usually evaluated at 14–21 days post infection. This approach fails to take account of the important effect of time on test performance after infection or exposure has occurred. We performed parallel serological testing using 4 widely used assays (a multiplexed SARS-CoV-2 Nucleoprotein (N), Spike (S) and Receptor Binding Domain assay from Meso Scale Discovery (MSD), the Roche Elecsys-Nucleoprotein (Roche-N) and Spike (Roche-S) assays and the Abbott Nucleoprotein assay (Abbott-N) on serial positive monthly samples collected as part of the Co-STARs study ( www.clinicaltrials.gov , NCT04380896) up to 200 days following infection. Our findings demonstrate the considerable effect of time since symptom onset on the diagnostic sensitivity of different assays. Using a time-to-event analysis, we demonstrated that 50% of the Abbott nucleoprotein assays will give a negative result after 175 days (median survival time 95% CI 168–185 days), compared to the better performance over time of the Roche Elecsys nucleoprotein assay (93% survival probability at 200 days, 95% CI 88–97%). Assays targeting the spike protein showed a lower decline over the follow-up period, both for the MSD spike assay (97% survival probability at 200 days, 95% CI 95–99%) and the Roche Elecsys spike assay (95% survival probability at 200 days, 95% CI 93–97%). The best performing quantitative Roche Elecsys Spike assay showed no evidence of waning Spike antibody titers over the 200-day time course of the study. We have shown that compared to other assays evaluated, the Abbott-N assay fails to detect SARS-CoV-2 antibodies as time passes since infection. In contrast the Roche Elecsys Spike Assay and the MSD assay maintained a high sensitivity for the 200-day duration of the study. These limitations of the Abbott assay should be considered when quantifying the immune correlates of protection or the need for SARS-CoV-2 antibody therapy. The high levels of maintained detectable neutralizing spike antibody titers identified by the quantitative Roche Elecsys assay is encouraging and provides further evidence in support of long-lasting SARS-CoV-2 protection following natural infection. 

https://www.nature.com/articles/s41598-022-14351-2.pdf

The influence of time on the sensitivity of SARS-CoV-2 serological testing

Exophiala dermatitidis is increasingly isolated from cystic fibrosis (CF) respiratory samples. The decision to treat is hampered by limited evidence demonstrating the clinical significance of isolating E. dermatitidis. The objective was to assess the impact of E. dermatitidis isolation on the lung function of CF patients. The rate of lung function decline in the local CF population was calculated using historic lung function data. A control population who had never had E. dermatitidis cultured from the respiratory tract was compared with the E. dermatitidis group, calculating their rate of lung function decline before and after the first isolation of the organism. A total of 1840 lung function measurements were reviewed between the 31 E. dermatitidis group patients and 62 control patients. Their demographics were similar. The control group declined at a rate of −0.824 FEV1%/year. The rate of decline in the E. dermatitidis group prior to infection was −0.337 FEV1%/year (p = 0.2). However, post infection with E. dermatitidis, there was a significant increase in the rate of decline in lung function (−1.824 FEV1%/year, p < 0.01). The results suggest E. dermatitidis has a temporal relationship with accelerated rate of lung function decline. It is not clear if this is a cause or effect, but this accelerated rate of decline indicates a need for further investigation.

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The Presence of Exophiala dermatitidis in the Respiratory Tract of Cystic Fibrosis Patients Accelerates Lung Function Decline: A Retrospective Review of Lung Function

Rishi H‐P Dhillon

Papers

ESBLs: A Clear and Present Danger?

Fungal infections in the critically ill

The Influence of Time on the Sensitivity of SARS-CoV-2 Serological Testing

The influence of time on the sensitivity of SARS-CoV-2 serological testing

The Presence of Exophiala dermatitidis in the Respiratory Tract of Cystic Fibrosis Patients Accelerates Lung Function Decline: A Retrospective Review of Lung Function