Editorial

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3 pages, 196 KiB

Open AccessEditorial

Antimicrobial Resistance: We Must Pursue a Collaborative, Global Approach and Use a “One Health” Approach

by Dagan O Lonsdale and Jeffrey Lipman

Antibiotics 2019, 8(4), 237; https://doi.org/10.3390/antibiotics8040237 - 27 Nov 2019

Cited by 2 | Viewed by 2979

Abstract

Treating infection is a key part of the work of most clinicians [...] Full article

(This article belongs to the Special Issue Feature Paper in Antibiotics for 2019)

Research

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15 pages, 257 KiB

Open AccessArticle

How Can National Antimicrobial Stewardship Interventions in Primary Care Be Improved? A Stakeholder Consultation

by Aleksandra J. Borek, Marta Wanat, Anna Sallis, Diane Ashiru-Oredope, Lou Atkins, Elizabeth Beech, Susan Hopkins, Leah Jones, Cliodna McNulty, Karen Shaw, Esther Taborn, Christopher Butler, Tim Chadborn and Sarah Tonkin-Crine

Antibiotics 2019, 8(4), 207; https://doi.org/10.3390/antibiotics8040207 - 31 Oct 2019

Cited by 17 | Viewed by 5091

Abstract

Many antimicrobial stewardship (AMS) interventions have been implemented in England, facilitating decreases in antibiotic prescribing. Nevertheless, there is substantial variation in antibiotic prescribing across England and some healthcare organizations remain high prescribers of antibiotics. This study aimed to identify ways to improve AMS [...] Read more.

Many antimicrobial stewardship (AMS) interventions have been implemented in England, facilitating decreases in antibiotic prescribing. Nevertheless, there is substantial variation in antibiotic prescribing across England and some healthcare organizations remain high prescribers of antibiotics. This study aimed to identify ways to improve AMS interventions to further optimize antibiotic prescribing in primary care in England. Stakeholders representing different primary care settings were invited to, and 15 participated in, a focus group or telephone interview to identify ways to improve existing AMS interventions. Forty-five intervention suggestions were generated and 31 were prioritized for inclusion in an online survey. Fifteen stakeholders completed the survey appraising each proposed intervention using the pre-defined APEASE (i.e., Affordability, Practicability, Effectiveness, Acceptability, Safety, and Equity) criteria. The highest-rated nine interventions were prioritized as most promising and feasible, including: quality improvement, multidisciplinary peer learning, appointing AMS leads, auditing individual-level prescribing, developing tools for prescribing audits, improving inductions for new prescribers, ensuring consistent local approaches to antibiotic prescribing, providing online AMS training to all patient-facing staff, and increasing staff time available for AMS work with standardizing AMS-related roles. These prioritized interventions could be incorporated into existing national interventions or developed as stand-alone interventions to help further optimize antibiotic prescribing in primary care in England. Full article

(This article belongs to the Special Issue Feature Paper in Antibiotics for 2019)

17 pages, 244 KiB

Open AccessArticle

Combating Antimicrobial Resistance in Singapore: A Qualitative Study Exploring the Policy Context, Challenges, Facilitators, and Proposed Strategies

by Shweta Rajkumar Singh, Alvin Qijia Chua, Sok Teng Tan, Clarence C. Tam, Li Yang Hsu and Helena Legido-Quigley

Antibiotics 2019, 8(4), 201; https://doi.org/10.3390/antibiotics8040201 - 29 Oct 2019

Cited by 11 | Viewed by 5893

Abstract

Antimicrobial resistance (AMR) is a global public health threat that warrants urgent attention. However, the multifaceted nature of AMR often complicates the development and implementation of comprehensive policies. In this study, we describe the policy context and explore experts’ perspectives on the challenges, [...] Read more.

Antimicrobial resistance (AMR) is a global public health threat that warrants urgent attention. However, the multifaceted nature of AMR often complicates the development and implementation of comprehensive policies. In this study, we describe the policy context and explore experts’ perspectives on the challenges, facilitators, and strategies for combating AMR in Singapore. We conducted semi-structured interviews with 21 participants. Interviews were transcribed verbatim and were analyzed thematically, adopting an interpretative approach. Participants reported that the Ministry of Health (MOH) has effectively funded AMR control programs and research in all public hospitals. In addition, a preexisting One Health platform, among MOH, Agri-Food & Veterinary Authority (restructured to form the Singapore Food Agency and the Animal & Veterinary Service under NParks in April 2019), National Environment Agency, and Singapore’s National Water Agency, was perceived to have facilitated the coordination and formulation of Singapore’s AMR strategies. Nonetheless, participants highlighted that the success of AMR strategies is compounded by various challenges such as surveillance in private clinics, resource constraints at community-level health facilities, sub-optimal public awareness, patchy regulation on antimicrobial use in animals, and environmental contamination. This study shows that the process of planning and executing AMR policies is complicated even in a well-resourced country such as Singapore. It has also highlighted the increasing need to address the social, political, cultural, and behavioral aspects influencing AMR. Ultimately, it will be difficult to design policy interventions that cater for the needs of individuals, families, and the community, unless we understand how all these aspects interact and shape the AMR response. Full article

(This article belongs to the Special Issue Feature Paper in Antibiotics for 2019)

15 pages, 692 KiB

Open AccessArticle

The Contribution of Efflux Pumps in Mycobacterium abscessus Complex Resistance to Clarithromycin

by Júlia S. Vianna, Diana Machado, Ivy B. Ramis, Fábia P. Silva, Dienefer V. Bierhals, Michael Andrés Abril, Andrea von Groll, Daniela F. Ramos, Maria Cristina S. Lourenço, Miguel Viveiros and Pedro E. Almeida da Silva

Antibiotics 2019, 8(3), 153; https://doi.org/10.3390/antibiotics8030153 - 18 Sep 2019

Cited by 25 | Viewed by 4530

Abstract

The basis of drug resistance in Mycobacterium abscessus is still poorly understood. Nevertheless, as seen in other microorganisms, the efflux of antimicrobials may also play a role in M. abscessus drug resistance. Here, we investigated the role of efflux pumps in clarithromycin resistance [...] Read more.

The basis of drug resistance in Mycobacterium abscessus is still poorly understood. Nevertheless, as seen in other microorganisms, the efflux of antimicrobials may also play a role in M. abscessus drug resistance. Here, we investigated the role of efflux pumps in clarithromycin resistance using nine clinical isolates of M. abscessus complex belonging to the T28 erm(41) sequevar responsible for the inducible resistance to clarithromycin. The strains were characterized by drug susceptibility testing in the presence/absence of the efflux inhibitor verapamil and by genetic analysis of drug-resistance-associated genes. Efflux activity was quantified by real-time fluorometry. Efflux pump gene expression was studied by RT-qPCR upon exposure to clarithromycin. Verapamil increased the susceptibility to clarithromycin from 4- to ≥64-fold. The efflux pump genes MAB_3142 and MAB_1409 were found consistently overexpressed. The results obtained demonstrate that the T28 erm(41) polymorphism is not the sole cause of the inducible clarithromycin resistance in M. abscessus subsp. abscessus or bolletii with efflux activity providing a strong contribution to clarithromycin resistance. These data highlight the need for further studies on M. abscessus efflux response to antimicrobial stress in order to implement more effective therapeutic regimens and guidance in the development of new drugs against these bacteria. Full article

(This article belongs to the Special Issue Feature Paper in Antibiotics for 2019)

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13 pages, 1410 KiB

Open AccessArticle

Antimicrobial Activity of Silver Camphorimine Complexes against Candida Strains

by Joana P. Costa, M. Joana F. Pinheiro, Sílvia A. Sousa, Ana M. Botelho do Rego, Fernanda Marques, M. Conceição Oliveira, Jorge H. Leitão, Nuno P. Mira and M. Fernanda N. N. Carvalho

Antibiotics 2019, 8(3), 144; https://doi.org/10.3390/antibiotics8030144 - 10 Sep 2019

Cited by 16 | Viewed by 4202

Abstract

Hydroxide [Ag(OH)L] (L = ^IVL, ^VL, ^VIL, ^VIIL), oxide [{AgL}₂}(μ-O)] (L = ^IL, ^IIL, ^IIIL, ^VL, ^VIL) or chloride [Ag^IIL]Cl, [Ag(^VIL)₂]Cl complexes were obtained from reactions [...] Read more.

Hydroxide [Ag(OH)L] (L = ^IVL, ^VL, ^VIL, ^VIIL), oxide [{AgL}₂}(μ-O)] (L = ^IL, ^IIL, ^IIIL, ^VL, ^VIL) or chloride [Ag^IIL]Cl, [Ag(^VIL)₂]Cl complexes were obtained from reactions of mono- or bicamphorimine derivatives with Ag(OAc) or AgCl. The new complexes were characterized by spectroscopic (NMR, FTIR) and elemental analysis. X-ray photoelectron spectroscopy (XPS), ESI mass spectra and conductivity measurements were undertaken to corroborate formulations. The antimicrobial activity of complexes and some ligands were evaluated towards Candida albicans and Candida glabrata, and strains of the bacterial species Escherichia coli, Burkholderia contaminans, Pseudomonas aeruginosa and Staphylococcus aureus based on the Minimum Inhibitory Concentrations (MIC). Complexes displayed very high activity against the Candida species studied with the lowest MIC values (3.9 µg/mL) being observed for complexes 9 and 10A against C. albicans. A significant feature of these redesigned complexes is their ability to sensitize C. albicans, a trait that was not found for the previously investigated [Ag(NO₃)L] complexes. The MIC values of the complexes towards bacteria were in the range of those of [Ag(NO₃)L] and well above those of the precursors Ag(OAc) or AgCl. The activity of the complexes towards normal fibroblasts V79 was evaluated by the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay. Results showed that the complexes have a significant cytotoxicity. Full article

(This article belongs to the Special Issue Feature Paper in Antibiotics for 2019)

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8 pages, 207 KiB

Open AccessArticle

Assessing National Antimicrobial Resistance Campaigns Using a Health Equity Assessment Tool (HEAT)

by Graeme Hood, Lina Toleikyte and Diane Ashiru-Oredope

Antibiotics 2019, 8(3), 121; https://doi.org/10.3390/antibiotics8030121 - 17 Aug 2019

Cited by 3 | Viewed by 3230

Abstract

It has been widely recognised that a significant proportion of the world’s population suffer inequalities in accessing high quality healthcare and wider services. Within healthcare, antimicrobial resistance (AMR) is a global threat to public health affecting all healthcare systems and growing at an [...] Read more.

It has been widely recognised that a significant proportion of the world’s population suffer inequalities in accessing high quality healthcare and wider services. Within healthcare, antimicrobial resistance (AMR) is a global threat to public health affecting all healthcare systems and growing at an alarming pace. To ensure that national AMR campaigns developed by Public Health England are inclusive of all populations within the target audience a health equity assessment tool (HEAT) was used. The project leads for each campaign completed the HEAT independently with a follow up meeting with the study team to discuss and clarify the responses. A trend analysis was carried out with common themes being used to provide recommendations. The campaigns have demonstrated equality and diversity based on the requirements of the Equality Act 2010, particularly age, sex, and race protected characteristics. Some notable results include the translation of website materials in over 30 languages and reaching individuals in 122 countries. It was however noted that several of the protected characteristics were not applicable. The continuous development of resources with collaboration from a variety of diverse user groups would be advantageous towards aiding future campaign reach. The use of the HEAT has demonstrated the ease and cost-effective way to assess any health inequalities and would be a useful addition to antimicrobial stewardship and public health campaigns. Full article

(This article belongs to the Special Issue Feature Paper in Antibiotics for 2019)

8 pages, 190 KiB

Open AccessArticle

General Practitioners’ Attitudes toward Municipal Initiatives to Improve Antibiotic Prescribing—A Mixed-Methods Study

by Marthe Sunde, Marthe Marie Nygaard and Sigurd Høye

Antibiotics 2019, 8(3), 120; https://doi.org/10.3390/antibiotics8030120 - 17 Aug 2019

Cited by 7 | Viewed by 3502

Abstract

Antimicrobial stewardship (AMS) interventions directed at general practitioners (GPs) contribute to an improved antibiotic prescribing. However, it is challenging to implement and maintain such interventions at a national level. Involving the municipalities’ Chief Medical Officer (MCMO) in quality improvement activities may simplify the [...] Read more.

Antimicrobial stewardship (AMS) interventions directed at general practitioners (GPs) contribute to an improved antibiotic prescribing. However, it is challenging to implement and maintain such interventions at a national level. Involving the municipalities’ Chief Medical Officer (MCMO) in quality improvement activities may simplify the implementation and maintenance, but may also be perceived challenging for the GPs. In the ENORM (Educational intervention in NORwegian Municipalities for antibiotic treatment in line with guidelines) study, MCMOs acted as facilitators of an AMS intervention for GPs. We explored GPs’ views on their own antibiotic prescribing, and their views on MCMO involvement in improving antibiotic prescribing in general practice. This is a mixed-methods study combining quantitative and qualitative data from two data sources: e-mail interviews with 15 GPs prior to the ENORM intervention, and online-form answers to closed and open-ended questions from 132 GPs participating in the ENORM intervention. The interviews and open-ended responses were analyzed using systematic text condensation. Many GPs admitted to occasionally prescribing antibiotics without medical indication, mainly due to pressure from patients. Too liberal treatment guidelines were also seen as a reason for overtreatment. The MCMO was considered a suitable and acceptable facilitator of quality improvement activities in general practice, and their involvement was regarded as unproblematic (scale 0 (very problematic) to 10 (not problematic at all): mean 8.2, median 10). GPs acknowledge the need and possibility to improve their own antibiotic prescribing, and in doing so, they welcome engagement from the municipality. MCMOs should be involved in quality improvement and AMS in general practice. Full article

(This article belongs to the Special Issue Feature Paper in Antibiotics for 2019)

12 pages, 1150 KiB

Open AccessArticle

Qualitative Analysis of Primary Care Provider Prescribing Decisions for Urinary Tract Infections

by Larissa Grigoryan, Susan Nash, Roger Zoorob, George J. Germanos, Matthew S. Horsfield, Fareed M. Khan, Lindsey Martin and Barbara W. Trautner

Antibiotics 2019, 8(2), 84; https://doi.org/10.3390/antibiotics8020084 - 19 Jun 2019

Cited by 23 | Viewed by 6186

Abstract

Inappropriate choices and durations of therapy for urinary tract infections (UTI) are a common and widespread problem. In this qualitative study, we sought to understand why primary care providers (PCPs) choose certain antibiotics or durations of treatment and the sources of information they [...] Read more.

Inappropriate choices and durations of therapy for urinary tract infections (UTI) are a common and widespread problem. In this qualitative study, we sought to understand why primary care providers (PCPs) choose certain antibiotics or durations of treatment and the sources of information they rely upon to guide antibiotic-prescribing decisions. We conducted semi-structured interviews with 18 PCPs in two family medicine clinics focused on antibiotic-prescribing decisions for UTIs. Our interview guide focused on awareness and familiarity with guidelines (knowledge), acceptance and outcome expectancy (attitudes), and external barriers. We followed a six-phase approach to thematic analysis, finding that many PCPs believe that fluoroquinolones achieve more a rapid and effective control of UTI symptoms than trimethoprim-sulfamethoxazole or nitrofurantoin. Most providers were unfamiliar with fosfomycin as a possible first-line agent for the treatment of acute cystitis. PCPs may be misled by advanced patient age, diabetes, and recurrent UTIs to make inappropriate choices for the treatment of acute cystitis. For support in clinical decision making, few providers relied on guidelines, preferring instead to have decision support embedded in the electronic medical record. Knowing the PCPs’ knowledge gaps and preferred sources of information will guide the development of a primary care-specific antibiotic stewardship intervention for acute cystitis. Full article

(This article belongs to the Special Issue Feature Paper in Antibiotics for 2019)

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10 pages, 235 KiB

Open AccessArticle

Antibiotic Prescribing Quality in Out-of-Hours Primary Care and Critical Appraisal of Disease-Specific Quality Indicators

by Annelies Colliers, Niels Adriaenssens, Sibyl Anthierens, Stephaan Bartholomeeusen, Hilde Philips, Roy Remmen and Samuel Coenen

Antibiotics 2019, 8(2), 79; https://doi.org/10.3390/antibiotics8020079 - 12 Jun 2019

Cited by 18 | Viewed by 4188

Abstract

Outpatient antibiotic use in Belgium is among the highest in Europe. The most common reason for an encounter in out-of-hours (OOH) primary care is an infection. In this study, we assessed all consultations from July 2016 to June 2018 at five OOH services. [...] Read more.

Outpatient antibiotic use in Belgium is among the highest in Europe. The most common reason for an encounter in out-of-hours (OOH) primary care is an infection. In this study, we assessed all consultations from July 2016 to June 2018 at five OOH services. We described antibiotic prescribing by diagnosis, calculated disease-specific antibiotic prescribing quality indicators’ (APQI) values and critically appraised these APQI. We determined that 111,600 encounters resulted in 26,436 (23.7%) antibiotic prescriptions. The APQI diagnoses (i.e., bronchitis, upper respiratory infection, cystitis, tonsillitis, sinusitis, otitis media, and pneumonia) covered 14,927 (56.7%) antibiotic prescriptions. Erysipelas (1344 (5.1%)) and teeth/gum disease (982 (3.7%)) covered more prescriptions than sinusitis or pneumonia. Over 75% of patients with tonsillitis and over 50% with bronchitis, sinusitis, and otitis media were prescribed an antibiotic. Only for otitis media the choice of antibiotic was near the acceptable range. Over 10% of patients with bronchitis or pneumonia and over 25% of female patients with an acute cystitis received quinolones. The APQI cover the diagnoses for only 57% of all antibiotic prescriptions. As 5.1% and 3.7% of antibiotic prescriptions are made for erysipelas and teeth/gum disease, respectively, we propose to add these indications when assessing antibiotic prescribing quality in OOH primary care. Full article

(This article belongs to the Special Issue Feature Paper in Antibiotics for 2019)

9 pages, 1705 KiB

Open AccessArticle

Determination of Florfenicol, Thiamfenicol and Chloramfenicol at Trace Levels in Animal Feed by HPLC–MS/MS

by Rosa Elvira Gavilán, Carolina Nebot, Ewelina Patyra, Beatriz Vazquez, Jose Manuel Miranda and Alberto Cepeda

Antibiotics 2019, 8(2), 59; https://doi.org/10.3390/antibiotics8020059 - 07 May 2019

Cited by 13 | Viewed by 4852

Abstract

Administration of florfenicol and thiamfenicol through medicated feed is permitted within the European Union, always following veterinary prescription and respecting the withdrawal periods. However, the presence of low levels of florfenicol, thiamfenicol, and chloramfenicol in non-target feed is prohibited. Since cross-contamination can occur [...] Read more.

Administration of florfenicol and thiamfenicol through medicated feed is permitted within the European Union, always following veterinary prescription and respecting the withdrawal periods. However, the presence of low levels of florfenicol, thiamfenicol, and chloramfenicol in non-target feed is prohibited. Since cross-contamination can occur during the production of medicated feed and according to Annex II of the European Regulation 2019/4/EC, the control of residue levels of florfenicol and thiamfenicol in non-target feed should be monitored and avoided. Based on all the above, a sensitive and reliable method using liquid chromatography tandem mass spectrometry was developed for the simultaneous detection of chloramfenicol, florfenicol, and thiamfenicol at trace levels in animal feed. Analytes were extracted from minced feed with ethyl acetate. Then, the ethyl acetate was evaporated, the residue was resuspended in Milli-Q water and the extract filtered. The method was in-house validated at carryover levels, with concentration ranging from 100 to 1000 µg/kg. The validation was conducted following the European Commission Decision 2002/657/EC and all performance characteristics were successfully satisfied. The capability of the method to detect amfenicols at lower levels than any prior perspective regulation literature guarantees its applicability in official control activities. The developed method has been applied to non-compliant feed samples with satisfactory results. Full article

(This article belongs to the Special Issue Feature Paper in Antibiotics for 2019)

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12 pages, 1112 KiB

Open AccessArticle

Antimicrobial and Synergistic Effects of Commercial Piperine and Piperlongumine in Combination with Conventional Antimicrobials

by Eunice Ego Mgbeahuruike, Milla Stålnacke, Heikki Vuorela and Yvonne Holm

Antibiotics 2019, 8(2), 55; https://doi.org/10.3390/antibiotics8020055 - 04 May 2019

Cited by 45 | Viewed by 8122

Abstract

Microbial resistance to currently available antibiotics is a public health problem in the fight against infectious diseases. Most antibiotics are characterized by numerous side effects that may be harmful to normal body cells. To improve the efficacy of these antibiotics and to find [...] Read more.

Microbial resistance to currently available antibiotics is a public health problem in the fight against infectious diseases. Most antibiotics are characterized by numerous side effects that may be harmful to normal body cells. To improve the efficacy of these antibiotics and to find an alternative way to minimize the adverse effects associated with most conventional antibiotics, piperine and piperlongumine were screened in combination with conventional rifampicin, tetracycline, and itraconazole to evaluate their synergistic, additive, or antagonistic interactions against Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans. The fractional inhibitory concentration index was used to estimate the synergistic effects of various combination ratios of the piperamides and antibiotics against the bacterial and fungal strains. Both piperine and piperlongumine showed synergistic effects against S. aureus when combined at various ratios with rifampicin. Synergistic interaction was also observed with piperine in combination with tetracycline against S. aureus, while antagonistic interaction was recorded for piperlongumine and tetracycline against S. aureus. All the piperamide/antibacterial combinations tested against P. aeruginosa showed antagonistic effects, with the exception of piperine and rifampicin, which recorded synergistic interaction at a ratio of 9:1 rifampicin/piperine. No synergistic interaction was observed when the commercial compounds were combined with itraconazole and tested against C. albicans. The results showed that piperine and piperlongumine are capable of improving the effectiveness of rifampicin and tetracycline. Dosage combinations of these bioactive compounds with the antibiotics used may be a better option for the treatment of bacterial infections that aims to minimize the adverse effects associated with the use of these conventional antibacterial drugs. Full article

(This article belongs to the Special Issue Feature Paper in Antibiotics for 2019)

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11 pages, 391 KiB

Open AccessArticle

Measuring Appropriate Antibiotic Prescribing in Acute Hospitals: Development of a National Audit Tool Through a Delphi Consensus

by Graeme Hood, Kieran S. Hand, Emma Cramp, Philip Howard, Susan Hopkins and Diane Ashiru-Oredope

Antibiotics 2019, 8(2), 49; https://doi.org/10.3390/antibiotics8020049 - 29 Apr 2019

Cited by 15 | Viewed by 5535

Abstract

This study developed a patient-level audit tool to assess the appropriateness of antibiotic prescribing in acute National Health Service (NHS) hospitals in the UK. A modified Delphi process was used to evaluate variables identified from published literature that could be used to support [...] Read more.

This study developed a patient-level audit tool to assess the appropriateness of antibiotic prescribing in acute National Health Service (NHS) hospitals in the UK. A modified Delphi process was used to evaluate variables identified from published literature that could be used to support an assessment of appropriateness of antibiotic use. At a national workshop, 22 infection experts reached a consensus to define appropriate prescribing and agree upon an initial draft audit tool. Following this, a national multidisciplinary panel of 19 infection experts, of whom only one was part of the workshop, was convened to evaluate and validate variables using questionnaires to confirm the relevance of each variable in assessing appropriate prescribing. The initial evidence synthesis of published literature identified 25 variables that could be used to support an assessment of appropriateness of antibiotic use. All the panel members reviewed the variables for the first round of the Delphi; the panel accepted 23 out of 25 variables. Following review by the project team, one of the two rejected variables was rephrased, and the second neutral variable was re-scored. The panel accepted both these variables in round two with a 68% response rate. Accepted variables were used to develop an audit tool to determine the extent of appropriateness of antibiotic prescribing at the individual patient level in acute NHS hospitals through infection expert consensus based on the results of a Delphi process. Full article

(This article belongs to the Special Issue Feature Paper in Antibiotics for 2019)

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Review

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52 pages, 2964 KiB

Open AccessReview

Actinomycete-Derived Polyketides as a Source of Antibiotics and Lead Structures for the Development of New Antimicrobial Drugs

by Helene L. Robertsen and Ewa M. Musiol-Kroll

Antibiotics 2019, 8(4), 157; https://doi.org/10.3390/antibiotics8040157 - 20 Sep 2019

Cited by 40 | Viewed by 12195

Abstract

Actinomycetes are remarkable producers of compounds essential for human and veterinary medicine as well as for agriculture. The genomes of those microorganisms possess several sets of genes (biosynthetic gene cluster (BGC)) encoding pathways for the production of the valuable secondary metabolites. A significant [...] Read more.

Actinomycetes are remarkable producers of compounds essential for human and veterinary medicine as well as for agriculture. The genomes of those microorganisms possess several sets of genes (biosynthetic gene cluster (BGC)) encoding pathways for the production of the valuable secondary metabolites. A significant proportion of the identified BGCs in actinomycetes encode pathways for the biosynthesis of polyketide compounds, nonribosomal peptides, or hybrid products resulting from the combination of both polyketide synthases (PKSs) and nonribosomal peptide synthetases (NRPSs). The potency of these molecules, in terms of bioactivity, was recognized in the 1940s, and started the “Golden Age” of antimicrobial drug discovery. Since then, several valuable polyketide drugs, such as erythromycin A, tylosin, monensin A, rifamycin, tetracyclines, amphotericin B, and many others were isolated from actinomycetes. This review covers the most relevant actinomycetes-derived polyketide drugs with antimicrobial activity, including anti-fungal agents. We provide an overview of the source of the compounds, structure of the molecules, the biosynthetic principle, bioactivity and mechanisms of action, and the current stage of development. This review emphasizes the importance of actinomycetes-derived antimicrobial polyketides and should serve as a “lexicon”, not only to scientists from the Natural Products field, but also to clinicians and others interested in this topic. Full article

(This article belongs to the Special Issue Feature Paper in Antibiotics for 2019)

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20 pages, 1383 KiB

Open AccessReview

Bacteriophages as Alternatives to Antibiotics in Clinical Care

by Danitza Romero-Calle, Raquel Guimarães Benevides, Aristóteles Góes-Neto and Craig Billington

Antibiotics 2019, 8(3), 138; https://doi.org/10.3390/antibiotics8030138 - 04 Sep 2019

Cited by 121 | Viewed by 18159

Abstract

Antimicrobial resistance is increasing despite new treatments being employed. With a decrease in the discovery rate of novel antibiotics, this threatens to take humankind back to a “pre-antibiotic era” of clinical care. Bacteriophages (phages) are one of the most promising alternatives to antibiotics [...] Read more.

Antimicrobial resistance is increasing despite new treatments being employed. With a decrease in the discovery rate of novel antibiotics, this threatens to take humankind back to a “pre-antibiotic era” of clinical care. Bacteriophages (phages) are one of the most promising alternatives to antibiotics for clinical use. Although more than a century of mostly ad-hoc phage therapy has involved substantial clinical experimentation, a lack of both regulatory guidance standards and effective execution of clinical trials has meant that therapy for infectious bacterial diseases has yet to be widely adopted. However, several recent case studies and clinical trials show promise in addressing these concerns. With the antibiotic resistance crisis and urgent search for alternative clinical treatments for bacterial infections, phage therapy may soon fulfill its long-held promise. This review reports on the applications of phage therapy for various infectious diseases, phage pharmacology, immunological responses to phages, legal concerns, and the potential benefits and disadvantages of this novel treatment. Full article

(This article belongs to the Special Issue Feature Paper in Antibiotics for 2019)

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19 pages, 792 KiB

Open AccessReview

Direct Measurement of Performance: A New Era in Antimicrobial Stewardship

by Majdi N. Al-Hasan, Hana Rac Winders, P. Brandon Bookstaver and Julie Ann Justo

Antibiotics 2019, 8(3), 127; https://doi.org/10.3390/antibiotics8030127 - 24 Aug 2019

Cited by 19 | Viewed by 7153

Abstract

For decades, the performance of antimicrobial stewardship programs (ASPs) has been measured by incidence rates of hospital-onset Clostridioides difficile and other infections due to multidrug-resistant bacteria. However, these represent indirect and nonspecific ASP metrics. They are often confounded by factors beyond an ASP’s [...] Read more.

For decades, the performance of antimicrobial stewardship programs (ASPs) has been measured by incidence rates of hospital-onset Clostridioides difficile and other infections due to multidrug-resistant bacteria. However, these represent indirect and nonspecific ASP metrics. They are often confounded by factors beyond an ASP’s control, such as changes in diagnostic testing methods or algorithms and the potential of patient-to-patient transmission. Whereas these metrics remain useful for global assessment of healthcare systems, antimicrobial use represents a direct metric that separates the performance of an ASP from other safety and quality teams within an institution. The evolution of electronic medical records and healthcare informatics has made measurements of antimicrobial use a reality. The US Centers for Disease Control and Prevention’s initiative for reporting antimicrobial use and standardized antimicrobial administration ratio in hospitals is highly welcomed. Ultimately, ASPs should be evaluated based on what they do best and what they can control, that is, antimicrobial use within their own institution. This narrative review critically appraises existing stewardship metrics and advocates for adopting antimicrobial use as the primary performance measure. It proposes novel formulas to adjust antimicrobial use based on quality of care and microbiological burden at each institution to allow for meaningful inter-network and inter-facility comparisons. Full article

(This article belongs to the Special Issue Feature Paper in Antibiotics for 2019)

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16 pages, 1303 KiB

Open AccessReview

The Perfect Bacteriophage for Therapeutic Applications—A Quick Guide

by Lucía Fernández, Diana Gutiérrez, Pilar García and Ana Rodríguez

Antibiotics 2019, 8(3), 126; https://doi.org/10.3390/antibiotics8030126 - 23 Aug 2019

Cited by 87 | Viewed by 10271

Abstract

The alarming spread of multiresistant infections has kick-started the quest for alternative antimicrobials. In a way, given the steady increase in untreatable infectious diseases, success in this endeavor has become a matter of life and death. Perhaps we should stop searching for an [...] Read more.

The alarming spread of multiresistant infections has kick-started the quest for alternative antimicrobials. In a way, given the steady increase in untreatable infectious diseases, success in this endeavor has become a matter of life and death. Perhaps we should stop searching for an antibacterial panacea and explore a multifaceted strategy in which a wide range of compounds are available on demand depending on the specific situation. In the context of this novel tailor-made approach to combating bacterial pathogens, the once forgotten phage therapy is undergoing a revival. Indeed, the compassionate use of bacteriophages against seemingly incurable infections has been attracting a lot of media attention lately. However, in order to take full advantage of this strategy, bacteria’s natural predators must be taken from their environment and then carefully selected to suit our needs. In this review, we have explored the vast literature regarding phage isolation and characterization for therapeutic purposes, paying special attention to the most recent studies, in search of findings that hint at the most efficient strategies to identify suitable candidates. From this information, we will list and discuss the traits that, at the moment, are considered particularly valuable in phages destined for antimicrobial therapy applications. Due to the growing importance given to biofilms in the context of bacterial infections, we will dedicate a specific section to those characteristics that indicate the suitability of a bacteriophage as an antibiofilm agent. Overall, the objective is not just to have a large collection of phages, but to have the best possible candidates to guarantee elimination of the target pathogens. Full article

(This article belongs to the Special Issue Feature Paper in Antibiotics for 2019)

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16 pages, 2536 KiB

Open AccessReview

Present and Future of Carbapenem-resistant Enterobacteriaceae (CRE) Infections

by Beatriz Suay-García and María Teresa Pérez-Gracia

Antibiotics 2019, 8(3), 122; https://doi.org/10.3390/antibiotics8030122 - 19 Aug 2019

Cited by 170 | Viewed by 19341

Abstract

Carbapenem-resistant Enterobacteriaceae (CRE) have become a public health threat worldwide. There are three major mechanisms by which Enterobacteriaceae become resistant to carbapenems: enzyme production, efflux pumps and porin mutations. Of these, enzyme production is the main resistance mechanism. There are three main groups [...] Read more.

Carbapenem-resistant Enterobacteriaceae (CRE) have become a public health threat worldwide. There are three major mechanisms by which Enterobacteriaceae become resistant to carbapenems: enzyme production, efflux pumps and porin mutations. Of these, enzyme production is the main resistance mechanism. There are three main groups of enzymes responsible for most of the carbapenem resistance: KPC (Klebsiella pneumoniae carbapenemase) (Ambler class A), MBLs (Metallo-ß-Lactamases) (Ambler class B) and OXA-48-like (Ambler class D). KPC-producing Enterobacteriaceae are endemic in the United States, Colombia, Argentina, Greece and Italy. On the other hand, the MBL NDM-1 is the main carbapenemase-producing resistance in India, Pakistan and Sri Lanka, while OXA-48-like enzyme-producers are endemic in Turkey, Malta, the Middle-East and North Africa. All three groups of enzymes are plasmid-mediated, which implies an easier horizontal transfer and, thus, faster spread of carbapenem resistance worldwide. As a result, there is an urgent need to develop new therapeutic guidelines to treat CRE infections. Bearing in mind the different mechanisms by which Enterobacteriaceae can become resistant to carbapenems, there are different approaches to treat infections caused by these bacteria, which include the repurposing of already existing antibiotics, dual therapies with these antibiotics, and the development of new ß-lactamase inhibitors and antibiotics. Full article

(This article belongs to the Special Issue Feature Paper in Antibiotics for 2019)

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8 pages, 212 KiB

Open AccessCommentary

Challenges for Economic Evaluation of Health Care Strategies to Contain Antimicrobial Resistance

by Emily A. F. Holmes and Dyfrig A. Hughes

Antibiotics 2019, 8(4), 166; https://doi.org/10.3390/antibiotics8040166 - 27 Sep 2019

Cited by 11 | Viewed by 4230

Abstract

The threat of antimicrobial resistance has global health and economic consequences. Medical strategies to reduce unnecessary antibiotic prescribing, to conserve the effectiveness of current antimicrobials in the long term, inevitably result in short-term costs to health care providers. Economic evaluations of health care [...] Read more.

The threat of antimicrobial resistance has global health and economic consequences. Medical strategies to reduce unnecessary antibiotic prescribing, to conserve the effectiveness of current antimicrobials in the long term, inevitably result in short-term costs to health care providers. Economic evaluations of health care interventions therefore need to consider the short-term costs of interventions, to gain future benefits. This represents a challenge for health economists, not only in terms of the most appropriate methods for evaluation, but also in attributing the potential budget impact over time and considering health impacts on future populations. This commentary discusses the challenge of accurately capturing the cost-effectiveness of health care interventions aimed at tackling antimicrobial resistance. We reflect on methods to capture and incorporate the costs and health outcomes associated with antimicrobial resistance, the appropriateness of the quality-adjusted-life year (QALY), individual time preferences, and perspectives in economic evaluation. Full article

(This article belongs to the Special Issue Feature Paper in Antibiotics for 2019)

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