newsletter - Tufts

Fall 2015 Volume 33, No. 2

NEWSLETTER PUBLISHED CONTINUOUSLY SINCE 1983 BY THE ALLIANCE FOR THE PRUDENT USE OF ANTIBIOTICS

Strategies for improving antimicrobial stewardship FEATURE ARTICLES 3

Introduction to this issue Bonnie Marshall (APUA Staff)

4

Antibiotics in aquaculture: impacts and alternatives Mario Caruffo DVM and Paola Navarrete PhD, Assistant Professor, University of Chile, Santiago, Chile

8

Update: Nebulized antimicrobial drug delivery Philip D. Walson, Visiting Professor, Department of Clinical Pharmacology, University Medical Center, Goettingen, Germany

APUA HEADQUARTERS, CHAPTER & RESISTANCE NEWS

10

APUA Headquarters in Action

11

International Chapter Updates 

Chapter Spotlight: APUA-Bulgaria



APUA-South Africa

14

Resistance in the News

17

Upcoming Events

18

Publications of Interest

20

About Us

Support our work

In a study of 6 farmed seafood types appearing in U.S. markets and originating from 11 different countries, scientists from Arizona State University have discovered traces of 5 antibiotics, including oxytetracycline, 4epioxytetracycline, sulfadimethoxine, ormetoprim and virginiamycin. While still compliant with FDA regulations, these low-levels of antibiotic create concern over long-term resistance development. Read more about the impacts of antibiotics on fish microbiota and alternatives to their use in this issue’s article by Caruffo and Navarrete.

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“Preserving the Power of Antibiotics”® Chief Executives

Advisory Board (cont)

Supporting Chapters:

Stuart B. Levy, President Thomas F. O’Brien, Vice President

Jacobo Kupersztoch, USA Jay A. Levy, USA Scott McEwen, Canada Jos. W.M. van der Meer, The Netherlands Richard P. Novick, USA Iruka Okeke, USA & Nigeria Maria Eugenia Pinto, Chile Vidal Rodriguez-Lemoine, Venezuela José Ignacio Santos, Mexico Mervyn Shapiro, Israel K. B. Sharma, India Atef M. Shibl, Saudi Arabia E. John Threlfall, United Kingdom Alexander Tomasz, USA Thelma e. Tupasi, Philippines Anne K. Vidaver, USA Fu Wang, China Thomas E. Wellems, USA Bernd Wiedemann, Germany

APUA—Abu Dhabi APUA—South Korea Australian Society for Antimicrobials (APUA-Australia) British Society for Antimicrobial Chemotherapy (APUA-UK)

Board of Directors Stuart B. Levy, Chairman Sherwood Gorbach Bonnie Marshall Thomas F. O’Brien Arnold G. Reinhold Dennis Signorovitch Philip D. Walson Mary Wilson

APUA Staff Barbara Lapinskas, Administrative Director Jane Kramer, Program Director Kathleen Young, Projects Consultant Stuart B. Levy, Newsletter Editor Bonnie Marshall, Associate Editor Casi Kadangs, Assistant Editor

Advisory Board Jacques F. Acar, France Werner Arber, Switzerland Fernando Baquero, Spain Michael l. Bennish, USA Otto Cars, Sweden Patrice Courvalin, France Jose Ramiro Cruz, Guatemala Julian Davies, Canada Abdoulaye Djimde, Mali Paul Farmer, Haiti Walter Gilbert, USA Herman Goossens, Belgium Sherwood l. Gorbach, USA Ian M. Gould, Scotland George Jacoby, USA Sam Kariuki, Kenya Ellen L. Koenig, Dominican Republic Calvin M. Kunin, USA

APUA gratefully acknowledges unrestricted grants from corporate sponsors:

APUA Project Partnerships: The Bill and Melinda Gates Foundation The Pew Charitable Trusts U.S. National Institute of Health (NIH) Pan American Health Organization (PAHO) U.S. Agency for International DevelopLeadership Level ($20,000+) ment (USAID) Clorox Healthcare U.S. Department of Agriculture bioMérieux U.S. Office of Homeland Security National Biodefense Analysis and CounBenefactor Level ($15,000+) termeasures Center BacterioScan The World Bank World Health Organization (WHO) Supporter Level ($2,500+) Centers for Disease Control and PrevenCubist Pharmaceuticals tion (CDC) Da Volterra U.S. Food and Drug Administration Ministries of Health Join the APUA corporate partnership U.S. Defense Threat Reduction Agency

Disclaimer APUA accepts no legal responsibility for the content of any submitted articles, nor for the violation of any copyright laws by any person contributing to this newsletter. The mention of specific companies or of certain manufacturers' products does not imply that they are endorsed or recommended by APUA in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.

The APUA Newsletter (ISSN 1524-1424) © 2015 APUA Since 1983, the APUA Newsletter has been a continuous source of non-commercial information disseminated without charge to healthcare practitioners, researchers, and policy-makers worldwide. The Newsletter carries up-to-date scientific and clinical information on prudent antibiotic use, antibiotic access and effectiveness, and management of antibiotic resistance. The publication is translated into three languages and distributed to over 7,000 affiliated individuals in more than 100 countries. The material provided by APUA is designed for educational purposes only and should not be used or taken as medical advice. We encourage distribution with appropriate attribution to APUA. See previous editions of the Newsletter on the APUA website.

*APUA welcomes letters to the Editor. Please send us your thoughts and questions. Names will be published but not addresses. All letters may be edited for style and length. Phone: 617-636-0966 | Email: [email protected] | Website: www.apua.org 2 • The APUA Newsletter Vol. 33. No. 2 • © 2015 APUA

Introduction to this issue

by Bonnie Marshall (APUA staff)

This issue of the APUA Newsletter touches on two diverse

aerosolized antibiotics – a method of delivery that was first

topics related to antibiotic use, both environmentally and

explored in the 1950’s. Early attempts at aerosolization, using

clinically. The topic of antibiotics and their impacts on the

penicillin G, ticarcillin, ceftazidine and carbenicillin, were

aquaculture industry is addressed by Caruffo and Navarrete.

largely abandoned due to the severe side effect of

This issue has long festered in the shadows cast by the

bronchospasm and other poor outcomes that may have been

enormous focus placed on antibiotic growth promotion use in

due to shortcomings in methodology. The rise of ventilator-

food animal farms. The burgeoning fish farming industry—

associated pneumonia (pneumonia in a patient who has been

the fastest growing form of food production in the world—has

mechanically ventilated for at least 48h) due to multidrug

tripled in the previous two decades. Asia accounts for 89% of

resistant pathogens such as Acinetobacter baunannii and

production, with China as the largest producer. Up to 90% of

Pseudomonas

fish consumed in the U.S. is imported, and half of that is farm-

antimicrobial therapy have prompted a reexamination of this

raised. With its frequently unregulated and questionable

method for antibiotic delivery. Today - both jet and ultrasonic

antimicrobial use practices, the industry bears closer scrutiny

nebulizers effectively deliver therapeutic levels of drug in

as a potential contributor to the escalating antibiotic

>90% of patients with minimal systemic dispersion.

resistance problem.

article by Walson discusses current practices and the

Our second article discusses the status and future of

aeruginosa

and

the

need

for

targeted

The

continuing need for clinical trials to resolve some ongoing issues with the use of this mode of therapy.

Introduction • The APUA Newsletter Vol. 33. No. 2 • © 2015 APUA • 3

Antibiotics in aquaculture: impacts and alternatives Mario Caruffo, DVM and Paola Navarrete, PhD, Assistant Professor, Institute of Nutrition and Food Technology (INTA), University of Chile, Santiago, Chile

The aquaculture industry provides high quality protein for bil-

simulate important evolutionarily conserved responses in the

lions of people, with fish representing 20 percent of the daily

host.13 The main bacterial phyla found in the fish gut are

animal protein intake for about 3 billion.1 As a significant per-

Proteobacteria, Firmicutes, Bacteroidetes, Fusobacteria,

centage of wild fish stocks are experiencing depletion, nearly

Actinobacteria, Clostridia, Bacilli, and Verrucomicrobia.

50 percent of the world´s fish supply now derives from aqua-

Studies in germ-free fish have revealed the roles of this mi-

culture.2 Antibiotics in aquaculture have been used primarily as

crobiota, which include epithelial proliferation, the promotion

therapeutic and prophylactic agents, with varying regulations

of nutrient metabolism, and innate immune responses. 13-15

depending on the country, which complicates the determina-

Composition of the microbiota, in terms of the type of bacte-

tion of the actual quantities used. Some data show large varia-

ria present in the digestive tract, determines the host respons-

tions between countries, with use ranging from an estimated 1

es.13 Consequently, the eventual modification of the microbial

g per metric ton of production in Norway to 700 g per metric

composition by antibiotic treatment could lead to alteration in

3

ton in Vietnam. Chile is the second largest salmon producer following Norway, however, its antibiotic use is 60 times greater than the other three top salmon-producing countries combined (Norway, Scotland and British Columbia). 4,5 Antibiotics are primarily administered to fish via their food. Of this, an estimated 30% of total antibiotic, and 80% of the ingested, antibiotic-mediated feed reach the environment through unconsumed and unabsorbed food, respectively. 6 Antibiotics can remain active in water and sediments for long periods of time, depending on the concentration and type of the chemicals, with a large impact on biodiversity and selection of resistant bacteria.6 Studies examining the effect of antibiotics on the gut microbiota have shown similar impacts.

The gut microbiota of fish The gut microbiota of fish have been extensively studied by culture and molecular techniques.7-12 While bacterial concentrations are lower and diversity is less broad than in the mammalian intestinal microbiota, the gut microbiota of fish 4 • The APUA Newsletter Vol. 33. No. 2 © 2015 APUA • Aquaculture

host response.

Antibiotic effects on host microbiota Studies on the impacts of antibiotics on the gut microbiota in mammals have revealed not only modifications in bacterial load and composition,16 but also an increase in the risk or incidence of some diseases.17-23 Antibiotics generate similar changes in fish as well. The impacts of antibiotic on bacterial load differ, depending on the antibiotic type and its concentration, as well as the fish species involved. Oxolinic acid (OA), oxytetracycline (OTC) and sulphafurazole reportedly cause an increase in bacterial densities throughout the digestive tract of rainbow trout (Salmo gairdneri Richardson).24 In contrast, erythromycin and penicillin G both produced a rapid reduction of bacterial counts,24 as did three dosages of OA (6, 12, and 24 mg/kg over 7 days).25 The administration of OTC (3g/kg in diet over 3 weeks) to Atlantic salmon (Salmo salar L.) reduced significantly the total viable gut population.26 This reduction was greater in bacteria from digesta when compared to those associated with the mucosa—with

Table 1. Alternatives to antibiotics in aquaculture: major advantages and limitations

1

The most studied of the essential oils are thymol (thyme and oregano), cinnamaldehyde (cinnamon), anethole (anise), eugenol (clove), and carvacrol (oregano).

the greatest effect occurring in the distal intestinal digesta. 26 In

(Salmo salar).27 While the intestinal microbiota of untreated

our study, OTC (75 mg/kg for 10 days) did not affect the bac-

fish remained diverse (predominantly Pseudomonas, Acineto-

terial load of cultivable bacteria.27 The antibiotic growth pro-

bacter, Bacillus, Flavobacterium, Psychrobacter, and Bre-

moters flavomycin (20 mg/kg) and florfenicol (20 mg/kg), and

vundimonas/Caulobacter/Mycoplana) diversity in the OTC-

the combination of two (10+10 mg/kg), dramatically reduced

treated fish was markedly reduced and only the opportunistic

the total intestinal counts in hybrid tilapia.28

pathogens Aeromonas veronii bv. sobria and A. salmonicida

Studies show that antibiotics can also alter the composition of

were isolated.27 Antibiotic treatment markedly increased the

the gut microbiota of fish, triggering a reduction in bacterial

frequency of OTC-resistant bacteria from 0% pretreatment, to

diversity and enabling the proliferation of opportunistic or

60%, 33% and 25% on days 11, 21, and 28 post-treatment, res-

resistant bacteria. The administration of three dosages of OA

pectively. The most frequent resistant determinants identified

(6, 12, and 24 mg/kg over 7 days) in rainbow trout showed

were tetE (78%) and tetD/H (22%).27

that intestinal Aeromonas remained susceptible to OA.25 In contrast, OA stimulated the proliferation of OA-resistant A eromonas in output water. The authors suggest that the selection and emergence of this resistant bacteria occurred following the excretion of the feces, rather than within the fish intestines

Following 8 weeks of treatment with the growth promoters flavomycin (20 mg/kg) and florfenicol (20 mg/kg), and the combination of the two (10+10 mg/kg), bacterial diversity of the autochthonous intestinal microbiota of hybrid tilapia was affected

themselves.25

as demonstrated by changes in band presence and intensity in

We have examined the effect of OTC (75 mg/kg) administered

mg/kg) for 10 days to Solea senegalensis juveniles produced a

through feed for 10 days on the diversity of the cultivable bac-

significant reduction in bacterial richness, reflected by a re-

teria from the intestines of healthy juvenile Atlantic salmon

duced number of DGGE bands.29 The administration of this

DGGE gels.28 Alternatively, the oral administration of OTC (40

Caruffo & Navarrete • The APUA Newsletter Vol. 33. No. 2• © 2015 APUA • 5

antibiotic was also linked to an up-regulation of genes related to apoptosis.

29

The general concerns about the effect of intensive antibiotic use also include ornamental fish. Recently, antibiotic resistance genes were detected in the microbiota of carriage water from ornamental fish,30 suggesting this ecological niche as a potential source of antibiotic resistance.

Several alternatives to antibiotics have been developed for use in aquaculture. A brief summary of the currently available options, including their advantages and limitations, is described in Table 1. Some, such as probiotics, have been more intensively investigated, while other methods (e.g., antimicrobial peptides, bacteriocins, and phage therapy) are still in developmental phases, but hold a promising future. Although not all have been tested in aquaculture facilities, all are important prospects for developing

Alternative treatments to antibiotics Antibiotic resistance among bacterial pathogens and concerns over the extensive use of antibiotics in animal production, including aquaculture, have gained global interest. This is reflected by tighter regulations on the prophylactic use of antibiotics and their presence as residues in aquaculture-derived products. For a sustainable aquaculture industry, novel strategies to control bacterial infections are needed.

6 • The APUA Newsletter Vol. 33 No. 2 • © 2015 APUA • Aquaculture

new strategies that could be combined or used in rotation in order to maximize protection of animals, the environment, and public health, and to prevent further antibiotic resistance development. References 1. Food and Agriculture Organization of the United Nations. The Post2015 Development Agenda and the Millennium Development Goals (2015). Available at http://bit.ly/1on8pXW. Accessed September 9, 2015. 2. FAO/WHO. The State of World Fisheries and Aquaculture.

Opportunities and challenges. (2014). Available at http:// www.fao.org/3/d1eaa9a1-5a71-4e42-86c0-f2111f07de16/i3720e. 3. Defoirdt T, Sorgeloos P, Bossier P. Alternatives to antibiotics for the control of bacterial disease in aquaculture. Current Opinion in Microbiology. 2011; 14: 251-258. 4. Henriksson P, Troell M, Rico A. Antimicrobial use in aquaculture: Some complementing facts. Proc Natl Acad Sci 2015; 112: E3317. 5. Bridson P (2014) Seafood Watch. Four-Region Summary Document. Available at www.seafoodwatch.org/-/m/sfw/pdf/reports/ mba_seafoodwatch_farmedsalmonsummary.pdf. Accessed September 15, 2015. 6. Cabello F, Godfrey H, Tomova A, et al Antimicrobial use in aquaculture re-examined: its relevance to antimicrobial resistance and to animal and human health. Environ Microbiol. 2013; 15: 19171942. 7. Austin B. The Bacterial Microflora of Fish, Revised. The Scientific World J. 2006; 6: 931–945. 8. Ringø E, Sperstad S, Myklebust R, et al. Characterisation of the microbiota associated with intestine of Atlantic cod (Gadus morhua L.) The effect of fish meal, standard soybean meal and a bioprocessed soybean meal. Aquaculture. 2006; 261: 829–841. 9. Huber I, Spanggaard B, Appel K, et al. Phylogenetic analysis and in situ identification of the intestinal microbial community of rainbow trout (Oncorhynchus mykiss, Walbaum). J Appl Microbiol. 2004; 96: 117–132. 10. Merrifield D, Burnard D, Bradley G, et al. Microbial community diversity associated with the intestinal mucosa of farmed rainbow trout (Oncoryhnchus mykiss Walbaum). Aquaculture Res. 2009; 40: 1064-1072. 11. Romero J and Navarrete P. 16S rDNA-based analysis of dominant bacterial populations associated with early life stages of coho salmon (Oncorhynchus kisutch). Microb Ecol. 2006; 51: 422-430. 12. Ghanbari M, Kneifel W, and Domig K. A new view of the fish gut microbiome: advances from next-generation sequencing. Aquaculture. 2015; 448: 464-475. 13. Rawls J, Samuel B, and Gordon J. Gnotobiotic zebrafish reveal evolutionarily conserved responses to the gut microbiota. Proc Natl Acad Sci USA. 2004; 101: 4596-4601. 14. Semova I, Carten J, Stombaugh J, et al. Microbiota regulate intestinal absorption and metabolism of fatty acids in the zebrafish. Cell Host Microbe. 2012; 12:277-288. 15. Bates JM, Mittge E, Kuhlman J, et al. Distinct signals from the microbiota promote different aspects of zebrafish gut differentiation. Dev Biol. 2006; 297: 374-386. 16. Heinsen FA, Knecht H, Neulinger SC, et al. Dynamic changes of the luminal and mucosa-associated gut microbiota during and after antibiotic therapy with paromomycin. Gut Microbes. 2015; 6:243-254. 17. Modi S, Collins J, Relman D. Antibiotics and the gut microbiota. J Clin Invest. 2014; 124: 4212-4218. 18. Yin J, Wang S, Liao S, et al. Different dynamic patterns of βLactams, quinolones, glycopeptides and macrolides on mouse gut microbial diversity. PLoS One. 2015; 10:e0126712. 19. Card R, Mafura M, Hunt T, et al. Impact of ciprofloxacin and clindamycin administration on Gram-negative bacteria isolated from healthy volunteers and characterization of the resistance genes they harbor. Antimicrob Agents Chemother. 2015; 59: 4410-4416.

20. Candon S, Perez-Arroyo A, Marquet C, et al. Antibiotics in early life alter the gut microbiome and increase disease incidence in a spontaneous mouse model of autoimmune

insulin-dependent diabetes. PLoS One. 2015; 10: e0125448. 21. Hu X, Wang T, Liang S, et al. Antibiotic-induced imbalances in gut microbiota aggravates cholesterol accumulation and liver injuries in rats fed a high-cholesterol diet. Appl Microbiol Biotechnol. 2015 Jul 1. 22. Boursi B, Haynes K, Mamtani R, Yang YX. Impact of antibiotic exposure on the risk of colorectal cancer. Pharmaco epidemiol Drug Saf. 2015; 24: 534-542. 23. Boursi B, Mamtani R, Haynes K, Yang YX. The effect of past antibiotic exposure on diabetes risk. Eur J Endocrinol. 2015; 172: 639-648. 24. Austin B, and Alzahrani M. The effect of antimicrobial compounds on the gastrointestinal microflora of rainbw trout, Salmo gairdneri Richardson. J Fish Biol 1988; 8: 1137-1144. 25. Naviner M, Giraud E, Thorin C, et al. Effects of three dosages of oral oxolinic acid treatment on the selection of antibioticresistant Aeromonas: Experimental approach in farmed trout. Aquaculture. 2007; 269: 31–40. 26. Bakke-McKellep A, Penn M, Salas P, et al. Effects of dietary soyabean meal, inulin and oxytetracycline on intestinal microbiota and epithelial cell stress, apoptosis and proliferation in the teleost Atlantic salmon (Salmo salar L.). Br J Nutr. 2007; 97: 699-713. 27. Navarrete P, Mardones P, Opazo R, et al. Oxytetracycline treatment reduces bacterial diversity of intestinal microbiota of Atlantic salmon. J Aquat Anim Health. 2008; 20: 177-183. 28. He S, Zhou Z, Liu Y, et al. Effects of the antibiotic growth promoters flavomycin and florfenicol on the autochthonous intestinal microbiota of hybrid tilapia (Oreochromis niloticus ♀ x O. aureus ♂). Arch Microbiol. 2010; 192: 985–994. 29. Tapia-Paniagua S, Vidal S, Lobo C, et al. Dietary administration of the probiotic SpPdp11: Effects on the intestinal microbiota and immune-related gene expression of farmed Solea senegalensis treated with oxytetracycline. Fish Shellfish Immunol. 2015; 46: 449-458. 30. Gerzova L, Videnska P, Faldynova M, et al. Characterization of microbiota composition and presence of selected antibiotic resistance genes in carriage water of ornamental fish. PLoS ONE. 2014; 9: e103865. 31. Jia X, Patrzykat A, Devlin R, et al. Antimicrobial peptides protect coho salmon from V ibrio anguillarum infections. Appl Environ

Microbiol. 2000; 65: 1928-1932. 32. Sarmasik A. Antimicrobial peptides: a potential therapeutic alternative for the treatment of fish diseases. Turkish J Biolog. 2002; 26: 201-207 33. Dunham RA, Warr GW, Nichols A, et al. Enhanced bacterial disease resistance of transgenic channel catfish Ictaulurus punctatus possessing cecropin genes. Mar Biotechnol. 2002; 4: 338-344. 34. Sarmasik A, Warr G, Chen TT. Production of transgenic medaka with increased resistance to bacterial pathogens. Mar Biotechnol. 2002; 3: 310-322. 35. Falco A, Brocal I, Pérez L, et al. In vivo modulation of the rainbow trout (Oncorhynchus mykiss) immune response by the human alpha defensin 1, HNP1. Fish Shellfish Immunol. 2008; 24: 102-112.

Caruffo & Navarrete references continued on p. 13

Caruffo & Navarette • The APUA Newsletter Vol. 33. No. 2 • © 2015 APUA • 7

Update Nebulized antimicrobial drug delivery Philip D. Walson, MD, Visiting Professor, Department of Clinical Pharmacology, University Medical Center, Goettingen, Germany

Antimicrobial drugs are usually given by either oral or

the patient.7 There are major differences in the performance

intravenous routes. Increasing interest has been shown in the

of different methods and devices used to generate aerosols

inhaled route of administration using either drug powders or

(e.g., jet versus ultrasonic nebulizers) with respect to these

aerosols to treat a number of diseases including pneumonia and

factors. There are also drug, concentration and formulation

sinusitis, based on the possibility of achieving higher

factors that affect the efficiency of drug delivery to the

concentrations at the site of infection with less systemic drug

patients and which, therefore, can affect how much of an

exposure and less toxicity.1

administered drug is swallowed versus inhaled, as well as

While antiviral and antifungal drugs,2-4 as well as other drugs (e.g., bronchodilators, diuretics, surfactants, prostanoids, and vasoconstrictors) are also being given by inhalation, most studies involve antibiotics, so this article will concentrate on inhalation administration of antibiotics, especially given as aerosols rather than by use of dry powders.

how much drug is vented into the environment. 8 For these reasons, studies of aerosolized administration must control for drug/device-related differences. In addition, there may be concentration-independent, drugspecific effects on the efficacy of inhaled drug delivery. Experimental

evidence

in

rodents

shows

that

Aerosolized antibiotics: uses and efficacy

fluoroquinolones are more effective when aerosolized

Many antibiotics are routinely given as aerosols to patients

because they achieve high pulmonary fluid concentrations. 9

with cystic fibrosis (CF), including aminoglycosides (e.g.,

However, other authors have questioned whether there is

tobramycin and amikacin), colistin and aztreonam. A number

any biopharmaceutical advantage to nebulization versus

of other antibiotics (e.g., the fluoroquinolones, ciprofloxacin

intravenous use.10 These authors claimed that the several-

and levofloxacin) are also in development for aerosol use.5

fold increases they observed in rodent pulmonary fluid-to-

These and other antibiotics are being given to patients with

plasma concentration ratios of three fluoroquinolones were

ventilator-associated pneumonia (VAP), as well as to patients

not the result of inhalation use, but rather the result of

with multidrug-resistant bacterial infections when the minimal

pulmonary

inhibitory concentrations exceed those that can be safely

fluoroquinolones in pulmonary fluid. Clearly more studies

achieved intravenously.6 Aerosolized antibiotics are likewise

are needed to establish, in humans, which nebulized drugs

being used in patients with limited IV access and inability to

are more effective and why.

take oral medications, e.g., premature infants.

Research needed

Studies of aerosolized drug delivery, mostly done in neonates, have identified a number of drug delivery related factors that can influence the efficacy of aerosolized delivery, including particle size, flow rates, and device placement with respect to

efflux

transporters

that

concentrate

There are a number of other unknowns and concerns about the use of nebulized antibiotics. For example, aerosols increase environmental contamination. Skin punctures, for example, cannot be used to collect blood to monitor

8 • The APUA Newsletter Vol. 33. No. 2 • © 2015 APUA • Nebulized anti-microbial drug delivery

aminoglycoside concentrations in CF patients who use face

administer drugs or amounts that cannot be given safely by oral

mask-aerosolized

are

or intravenous use. However, there are a number of unknowns

While less of a

associated with inhalation therapy, including environmental

antibiotics

because

contaminated with the aerosolized drug.

their 11

fingers

problem with ventilator-administered drugs, contamination of the environment as well as health care workers can occur. Also, drug that is swallowed rather than inhaled (a variable that is not an insignificant percentage of the administered dose) exposes the patient’s oral and GI track mucosal bacteria to the drug and

impacts and the effects of medical staff exposure. Dr. Walson is a member of the APUA Board of Directors. He is also a paid consultant to Aerogen, a company that manufactures aerosol devices for medication delivery.

potentially, to those who handle the patient’s bodily fluids, stool, urine and waste. The fact that higher concentrations and

References:

total amounts can be used is an advantage therapeutically, but it

1. Hagerman JK, Hancock KE, Klepser ME. Aerosolised antibiotics: a critical appraisal of their use. Expert Opin. Drug Deliv. 2006;3:71–86.

is also a potential disadvantage with respect to the development of resistance. Effects on the exposure of health care workers, including cleaning staff, are particularly in need of study. There is very little known about the relative incidence of antibacterial resistance following inhalation compared with oral or intravenous administration. However, while concerns were raised when inhalation antibiotics were first used for CF patients, there has not been evidence yet of any increase, and it is at least theoretically possible that being able to use higher concentrations at the site of infection could actually decrease the development of resistance. Inhaled drugs are, as mentioned, being used successfully to treat multidrug-resistant pulmonary infections, which could subsequently decrease the spread of such organisms. Much needs to be done to clarify the relative risks of oral, IM, IV and inhalation use of antibiotics with respect to the development of resistance. Toxicity of chronic pulmonary exposure to aerosol excipients is another concern. Bronchospasm can occur for example and must be monitored for, but its recognition can be delayed, especially in ventilated patients.6 Exposure to aerosols could also be a problem for staff that are allergic to the administered drug or its excipients.

Conclusions Aerosolized antibiotics are being increasingly used based on the fact that this mode provides a way to deliver higher concentrations of drugs to the site of infection, as well as to

2. Ison MG, Clinical use of approved anti-influenza antivirals: therapy and prophylaxis, Influenza and Other Respiratory Viruses, 2012; 7 (Suppl. 1):7-13. 3. Englund, J., Piedra, P., Young-Min, A., Gilbert B. & Hiatt P, High-dose, short-duration ribavirin aerosol therapy compared with standard ribavirin therapy in children with suspected RSV infection. Journal of Pediatrics 1994;125, 635–41. 4. Le J and Schiller DS. Aerosolized Delivery of Antifungal Agents. Current Fungal Infection Reports, 2010;4:96-102. 5. Orlando Regional Medical Center, Dept. of Surgical Education. http://www.surgicalcriticalcare.net/Guidelines/ aerosolized_antibiotics_2009.pdf 6. Conway SP, Nebulized Antibiotics: the evidence. Chron Respir Dis. 2005;2:35-41 7. Mazela J and Polin RA, Aerosol delivery to ventilated newborn infants: historical challenges and new directions. Eur J Pediatr. 2011, 170(4):433–444. 8. Weber A, Morlin G, Cohen M, et al. Effect of nebulizer type and antibiotic concentration on device performance, Pediatr Pulmonol1997; 23:249-260 9. Sabet M, Miller CE, Nolan TG, et al. Efficacy of aerosol MP-376, a levofloxacin inhalation solution, in models of mouse lung infection due to Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 2009;53:3923–3928. 10. Gontijo AVL, Brillault J, Grégoire N, et al. Biopharmaceutical Characterization of Nebulized Antimicrobial Agents in Rats: Ciprofloxacin, Moxifloxacin, and Grepafloxacin, Antimicrob. Agents Chemother, 2014;58:3942-3949. 11. Walson PD. Practical aspects of neonatal therapeutic drug monitoring. In: Recent Developments in Therapeutic Drug Monitoring and Clinical Toxicology, ISunshine (ed.). Marcel Dekker, New York, 1992:65-70. Walson • The APUA Newsletter Vol. 33. No. 2 • © 2015 APUA • 9

APUA Headquarters in Action APUA staff attend Longitude Prize informational meeting

APUA supports multiple legislative initiatives

The Longitude Prize is a science challenge with a £10 million

into the U.S. Congress on Sept. 17. The "Reinvigorating

prize fund which aims to conserve antibiotics for future

Antibiotic and Diagnostic Innovation (READI) Act" would

generations

global

provide a tax incentive for qualifying manufacturers to increase

healthcare. Prize administrators, including Professor of Health

clinical testing of antibiotic and antifungal drugs and rapid

Law Kevin Outterson of Boston University School of Law,

diagnostics for infectious diseases. Signed by over 40

described the qualities judges sought in entries at a Harvard

supporting organizations, the letter emphasizes the need for

Business School promotional meeting. APUA’s Dr. Thomas

new antibiotic development and the need to provide incentives

O’Brien and Jane Kramer participated in the September event.

to spur this work. Read the Text for H.R.3539 here.

and

revolutionize

the

delivery

 APUA has added its support to the bi-partisan bill introduced

of

The Prize commemorates the 300th anniversary of the Longitude Act of 1714 when the British government challenged the public to solve the greatest scientific challenge, determining longitude at sea. In partnership with the BBC, the public voted for one of six of the biggest challenges today and chose antibiotic resistance to be the focus of the Longitude Prize in 2014. The challenge is to develop a point-of-care test

 In July, APUA, along with allied organizations, wrote to U.S. Representatives Lamar Alexander and Patty Murray urging them to include the bi-partisan “Promise for Antibiotics and Therapeutics for Health (PATH) Act” into broader legislation they are developing for the Innovation for Healthier Americans Initiative. Read the S.185 PATH Act here.

that will identify when antibiotics are needed and if they are,

 APUA has joined with Pew Charitable Trusts and other

which ones. Find out more about how you can get involved at

interested organizations in signing on to a letter in support of

longitudeprize.org Entries are still being accepted.

the Centers for Medicare and Medicaid (CMS) proposed rule

Clorox partners with APUA rd

(Federal Register CMS-3260-P) that would make stewardship programs a condition of participation for long-term care (LTC)

On September 3 , Clorox Healthcare issued a press release

facilities. Because long-term care residents are often prescribed

announcing its new partnership with APUA to raise awareness

antibiotics,

on the link between antimicrobial stewardship, environmental

stewardship programs to monitor and ensure appropriate

hygiene and infection control practices.

antibiotic use.

“Ours is a natural alliance because strengthening health systems and clinical practice by cleaning, disinfection and

LTC

facilities

should

implement

antibiotic

Transitions

process compliance reduces or prevents transmission of

APUA extends its deepest thanks to Dr. Gordon W.

resistant bacteria. There are strategies that APUA champions

Grundy as he completes 12 years of outstanding

globally and Clorox Healthcare helps realize,” said Stuart B. Levy, MD, President of APUA. “APUA and Clorox Healthcare will work together to raise

service as a member of APUA’s Board of Directors. His leadership, advice and enthusiasm have aided the organization immeasurably in forwarding its mission to preserve the power of antibiotics. As he leaves our

awareness of this important issue and strengthen educational

Board we wish him well in all his future endeavors.

programs that inform best practices in infection prevention and

Thank you Dr. Grundy!

antibiotic stewardship,” said Rosie Lyles, MD, MHA, MLSc, Head of Clinical Affairs for Clorox Healthcare. 10 • The APUA Newsletter Vol. 33. No. 2 • © 2015 APUA • APUA HQ in Action

International Chapter Updates Chapter Spotlight: APUA-Bulgaria Tularemia were recorded in Bulgaria during the past 10 years,

Founded: 1998

with seven new cases appearing since the beginning of 2015;

Bulgaria Leadership: President: Prof. Encho Savov, MD, PhD, DSc; Head, Dept. Military Epidemiology and Hygiene, Military Medical Academy, Sofia Co-ordinator: Prof. Emma Keuleyan, MD, PhD; Head, Dept. Clinical Microbiology, Medical Institute Ministry of the Interior; Assoc. Prof. Kalinka Bojkova, MD, PhD Head, Dept Microbiology and Virology, Medical University, Varna? Prof. Marianna Murdjeva MD, PhD, Vice-Rector on Scientific affairs; Assoc. Prof. Boyka Markova, MD, PhD Head, Clinical Microbiology Laboratory "Sinevo", Sofia Affiliations: Bulgarian Society for Medical Microbiology (BSMM), the Bulgarian Association of Microbiologists (BAM), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), European Society of Chemotherapy (and) Infectious Diseases (ESCiD), International Society of Chemotherapy (ISC) and others.

21 cases of Crimean-Congo hemorrhagic fever occurred over 4 years, but only one case of anthrax during the last decade. During 2014 the preparation for, diagnosis and management of potential Ebola viral disease received special attention, together with measures for infection control. Among vector-borne infections, there were 404 cases of Lyme borreliosis, 343 cases of Mediterranean spotted fever and 17 cases of Q fever in 2014. Within clinical bacteriology sessions, the most important focused on molecular mechanisms of antimicrobial resistance, particularly carbapenem resistance. Researchers have identified KPC-2 carbapenemase, VIM-1, OXA-48 and NDM-1 in Enterobacteriaceae strains, and Bla OXA23, OXA58 enzymes together with hypersecretion of OXA51 in Acinetobacter baumannii. It is worth noting that antibiotic policies have been developed in all hospitals as a national state requirement. Both microbiologists and infectious diseases specialists are active

Membership: 105

participants in scientific projects and forums dedicated to

APUA-Bulgaria chapter specialists in Clinical Microbiology,

preventing antimicrobial resistance. European Antibiotic Day is

Epidemiology and Infectious Diseases organized and/or

traditionally celebrated on November 18 and Medical

participated in the following scientific events during the first

University professors participate with specialized lectures and

half of 2015:

exercises on the issue.

 The scientific conference Particularly Dangerous

In conclusion, Bulgar-

Zoonoses in Bulgaria, held in Kostenec, March 17-18,

ian microbiologists, epi-

2015, (organized by the National Center for Infectious and

demiologists

Parasitic Diseases);

fectious diseases spec-

th

 The 8 National Congress of the Bulgarian Association of Microbiologists, Sofia, 16 - 18 April, 2015; and  The Jubilee scientific conference 70 years of Medical University – Plovdiv, Plovdiv, May 21-23, 2015. Emerging severe zooanthroponoses was one of several featured topics. Of note, 400 confirmed clinical cases of

ialists

share

and

in-

concern

about the problem of antimicrobial resistance and work to prevent further

development

Prof. Encho Savov President, APUA-Bulgaria

and spread. We seek to work with our international colleagues to contribute to resistance containment.

International Chapter Spotlight—Bulgaria • The APUA Newsletter Vol. 33 No. 2 • © 2015 APUA • 11

APUA-Bulgaria: Recent Publications  Deccache, Y., L. Irenge L, Savov E, Ariciuc M, Macovei A, Trifonova A, Gergova I, Ambroise J, Vanhoof R, Gala J-L. 2011 Development of a Pyrosequencing assay for rapid assessment of quinolone resistance in Acinetobacter baumannii isolates. J Microbiol Methods. 86. (1):115-8  Ivanov I, Sabtcheva S, Dobreva E, Todorova B, Velinov Tz, Borissova V et al. Prevalence of carbapenemase among 16S rRNA methyltransferase-producing Enterobacteriaceae isolated from cancer patients. Probl Infect Parasit Dis, 42, 2014,1: 10-13

Biotechnological Equipment. DOI: 10.5504/BBEQ/ WAP.2012.0001 MB  Savov E., I. Gergova, M. Borisova, E. Kjoseva, A. Trifonova, I. Todorova, K. Ramshev, N. Petrov. Consumption of antimicrobial drugs and antibiotic resistance in problematic hospital pathogens. Trakia J of Sciences, 2013, 4: 338-342  Savov E., Trifonova A, Todorova I. Gergova I. In vitro activity of levofloxacin, gemifloxacin, linezolid, vancomycin, dalbavancin and telavancin against Grampositive clinical isolates. Trakia J of Sciences, 2013, 4: 334337  Savov E, Trifonova A, Gergova I, Borissova M, Kioseva E, Todorova I. Antibiotic resistance, a world challenge. Preventive Med. 2, 2014, 7: 3-8

 Keuleyan E. Antibiotic resistance – a world healthcare problem. J Contemporary Medical Problems, 2014, 1: 53 62  Keuleyan E, Batashki I, Smilov N, Trenovska R, Mirchev M, Popov D. Ebola viral infection 2014 – from the African rainforests to world threat. J Contemporary Medical Problems, 2014, 2: 20 -35  Keuleyan E, Valentinova M, Tete Sh. Inquiry into“rational usage of antibiotics”. J Contemporary Medical Problems, 2014, 1: 6-13  Lesseva M, Argirova M, Nashev D, Zamfirova E, Hadjiiski O. Nosocomial infections in burn patients: aetiology, antimicrobial resistance, means to control. Ann Burns & Fire Disasters, 26, 2013, 1: 5-11

Members of the APUA-Bulgaria delegation

 Markovska R, Bauernfeind A, Bojkova K, Boyanova L, Schneider I, et al. First identification of KPC-2 and VIM-1 producing Klebsiella pneumoniae in Bulgaria. Diagn Microbiol Infect Dis, 77, 2013, 3: 252-253

APUA – South Africa

 Milanova M, Lesseva M. Antibiotic policies in cardiology. Cardio-vascular Dis. 64, 2013, 1: 30-35

South Africa published its Antimicrobial Resistance (AMR)

 Petrov M., A. Petrova, I. Stanimirova, M. Mircheva, L. Koycheva, R. Velcheva, M. Stoycheva, M. Murdjeva. Evaluation of antimicrobial resistance in Salmonella and Shigella isolates in St. George University Hospital Plovdiv, Bulgaria. Folia Medica, 2015, suppl.1, 57:61-62

This framework provides “a structure for managing AMR to

 Petrova A., I. Stanimirova, M. Mircheva, M. Petrov, V. Kardjeva, M. Murdjeva. Polymerase chain-reaction analysis of carbapenem resistance in Gram-negative non-fermenting isolates from St. George University hospital in Plovdiv. Folia Medica, 2015, suppl.1, 57: 64-65  Poirel L, Savov E, A.Nazli A, A.Trifonova A, I.Todorova I, I.Gergova I, P.Nordmann P. Outbreak caused by NDM-1 and RmtB-producing Escherichia coli in Bulgaria. Antimicrob Agents Chemother, 2014, doi:10.1128/ AAC.02571-13, 2472-2474  Savov E, Trifonova A, Todorova I,Gergova I, Borisova M, Kjoseva E, Tsekov I. Emergence of NDM-1-Producing Enterobacteriaceae in Bulgaria. Biotechnology &

Submitted by: Sabiha Essack, B. Pharm., M. Pharm., PhD

National Strategy Framework 2014-2024 in October 2014. limit further increases in resistant microbial infections and improve patient outcomes” via four strategic objectives:  Establish national and health establishment governance structures to strengthen, coordinate and institutionalize interdisciplinary AMR efforts;  Expand surveillance and early detection of AMR and enable reporting of resistance trends at local, regional and national levels to optimize empiric and targeted antibiotic choice;  Enhance infection prevention and control to contain the spread of resistant microbes to patients in healthcare

12 • The APUA Newsletter Vol. 33 No. 2 • © 2015 APUA • International Chapter Updates

settings, focusing on hand hygiene and patient isolation (Community measures include preventing infection through vaccination programmes and improvements in water and sanitation); and  Implement antimicrobial stewardship to promote appropriate use of antimicrobials in human and animal health. Health system strengthening is acknowledged as central to the success of the strategy and the interventions are underpinned by education (of health professionals within undergraduate and postgraduate curricula, as well as via continuous professional education courses), public awareness and

a

sustained

multi-pronged

information campaign.

communication

and

Oversight and governance are

mooted to ensure that the strategy is implemented in all relevant sectors.*

Signatories to the Framework are the

government Ministries of Health, Science and Technology and Agriculture Forestry and Fisheries, private and public Laboratory Services, Professional Societies, Regulatory Bodies and Civil Society. An implementation plan has been drafted using a results management framework which delineates outcomes, outputs, activities, indicators, time frames and responsible offices/persons as well as risks and risk mitigation strategies. The call for nominations for the Ministerial Advisory Committee which will have oversight of the implementation of the AMR framework is imminent.

*Department of Health (2014) Antimicrobial Resistance National Strategy Framework 2014-2024 Draft Document. Department of Health, Pretoria, South Africa.

Caruffo & Navarrete Refs cont. from p. 7 36. Nakai T, Park SC. Bacteriophage therapy of infectious diseases in aquaculture. Res Microbiol. 2002; 153: 13-18. 37. Vinod MG, Shivu MM, Umesha KR, et al. Isolation of V ibrio harveyi bacteriophage with a potential for biocontrol of luminous vibriosis in hatchery environments. Aquaculture. 2006; 255: 117-124. 38. Stenholm AR, Dalsgaard I, Middelboe M. Isolation and characterization of bacteriophages infecting the fish pathogen Flavobacterium psychrophilum. Appl Environ Microbiol. 2008; 74: 40704078. 39. Defoirdt T, Boon N, Sorgeloos P, et al. Short-chain fatty acids and poly-b-hydroxyalkanoates: (new) biocontrol agents for a sustainable animal production. Biotechnol Adv. 2009; 27: 680685. 40. Liu Y, De Schryver P, Van Delsen B, et al. PHB-degrading bacteria isolated from the gastrointestinal tract of aquatic animals as protective actors against luminescent vibriosis. FEMS Microbiol Ecol. 2010; 74: 196-204. 41. Desriac F, Defer D, Bourgougnon N, et al. Bacteriocin as weapons in the marine animal-associated bacteria warfare: Inventory and potential applications as an aquaculture probiotic. Mar Drugs. 2010; 8: 1153-1177. 42. Sahoo TK, Jena PK, Patel AK, Seshadri S. Bacteriocins and their applications for the treatment of bacterial diseases in aquaculture: a review. Aquaculture Res. 2014; doi: 10.1111/are.12556. 43. Verschuere L, Rombaut G, Sorgeloos P, Verstraete W. Probiotic bacteria as biological control agents in aquaculture. Microbiol Mol Biol Rev. 2000; 64: 655-6738. 44. Mohapatra S, Chakraborty T, Kumar V, et al. Aquaculture and stress management: a review of probiotic intervention. J Anim Physyiol Anim Nutr. 2013; 97: 405-430. 45. Hai NV. 2015. The use of probiotics in aquaculture. J Appl Microbiol. 28: doi: 10.1111/jam.12886. 46. Standen BT, Rodiles A, Peggs DL, et al. Modulation of the intestinal microbiota and morphology of tilapia, Oreochromis niloticus, following the application of a multi-species probiotic. Appl Microbiol Biotechnol. 2015; doi:10.1007/s00253-015-6702-2. 47. Immanuel G, Uma R, Iyapparaj P, et al. Dietary medicinal plant extracts improve growth, immune activity and survival of tilapia Oreochromis mossambicus. J Fish Biol. 2009; 74: 1462-1475. 48. Navarrete P, Toledo I, Mardones P, et al. Effect of Thymus vulgaris essential oil on intestinal bacterial microbiota of rainbow trout, Oncorhynchus mykiss (Walbaum) and bacterial isolates. Aquacult Res. 2010. 41: 667-678.

Coming Soon!

International Chapter Updates • The APUA Newsletter Vol. 33 No. 2 • © 2015 APUA • 13

Resistance in the News Point-of-care CRP test shows promise for reducing antibiotic prescriptions

Garlic compound shows promise in fight against multidrug-resistant pathogens

The UK group, Patients’ Association, has published a report

Scientists at the Birla Institute of Technology and Sciences in

which reveals that the use of point-of-care (POC) C-reactive

India have discovered that garlic, Allium sativum, has proper-

protein could potentially reduce the number of antibiotic pre-

ties that are effective in fighting multi-drug resistant bacteria

scriptions by 10 million. The use of this test would also save

that cause urinary tract infections (UTIs). More specifically,

the NHS £56 ($87.3) million in associated prescription and

the chemical allicin, which gives garlic its signature scent and

dispensing costs. The test is very simple, requiring a finger-

works to repel natural predators, is thought to be the key to the

prick blood sample with results available in a few minutes to

herb’s antibiotic properties.

help determine whether or not antibiotics are appropriate for treatment. The report further states that “despite the findings that POC CRP testing reduces inappropriate and unnecessary antibiotic prescribing in primary care…the UK continues to limit its use of the testing method”.

Published in Pertanika Journal of Tropical A gricultural Science, the article, Garlic: An Effective Functional Food to Combat the Growing Antimicrobial Resistance, describes a study of urinary tract pathogens (E. coli, Enterobacter sp, Klebsiella sp. S. aureus, and P. aeruginosa) with multidrug

The report goes on to make recommendations for policymak-

resistance to >4 of 7 agents tested. When exposed to allicin

ers, commissioners, and health professionals including:

extract in Kirby-Bauer disk diffusion assays, 82% of strains

 Routine use of POC CRP testing by health professionals and its integration into patient consultation;  Recognize the POC CRP testing could help clinical com-

showed susceptibility to the chemical. An earlier article in PlosOne (Garlic revisited: antimicrobial activity of allicin-containing garlic extracts against Burkhold-

missioning groups attain the Quality Premium and meet

eria cepaia complex) suggests that allicin has potential as an

the NHS quality agenda;

adjunct to existing antibiotics in the treatment of the intrinsi-

 Follow NICE guidelines for pneumonia, which supports combining primary care CRP POC testing with clinical diagnosis and history-taking to decide whether to prescribe antibiotics for lower respiratory tract infections; and  Collaborate with commissioners to develop local guidelines that support accurate differential diagnosis for respiratory tract infections. For a summary of APUA’s summit on point-of-care rapid

cally antibiotic-resistant Burkholderia infections that plague cystic fibrosis patients. The promising results are encouraging researchers to explore alternatives to the current cache of antimicrobials and to investigate a crucial factor—whether oral administration or injection provides the most effective delivery.

“Weaponized” Acinetobacter demonstrates self-limiting resistance

diagnostics including CRP, see APUA Newsletter Vol 32(2), 2014, p20 and the subsequent publication: Improving outpatient antibiotic prescribing for respiratory tract infections: results of new algorithms used in European trials by Drs. R Gaynes and S. Levy in Infect Control Hosp Epidemiol 2015 Jun 4;36(6):725-9.

In a recent PNAS study, researchers at the Washington University School of Medicine in St. Louis suggest that drugresistant bacteria can be self-limiting. The researchers focused on multidrug-resistant Acinetobacter baumannii, a leading hospital-acquired bacterium that also survives disinfectants,

News andinPublications 14 • The APUA Newsletter Vol. 33. No. 2 • © 2015 APUA • Resistance the News of Note • The APUA Newsletter Vol. 32. No. 1 • © 2014 APUA • 14

making it very difficult to treat. This organism carries a toxic type VI secretion system (T6SS) that acts as a survival strategy against bacterial competitors. In most strains, the system is repressed by regulators borne on a self-transmissible resistance plasmid, which also expresses multidrug resistance (MDR). However, when subjected to a hostile environment, a subset of cells spontaneously lose the plasmid, which activates the T6SS, but results in simultaneous loss of the MDR phenotype.

CDC issues 5-pronged Antibiotic Resistance Solutions Initiative The U.S. Centers for Disease Control and Prevention (CDC) are central to the Obama Administration’s National Action Plan for Combating Antibiotic Resistant Bacteria (CARB). As such, $264 million has been earmarked for the agency’s comprehensive response to fighting resistance.

Further studies on samples from outbreaks across the globe

The response strategy, aptly named the Antibiotic Resistance

showed the same pattern. The discovery that such superbugs

Solutions Initiative, is comprised of 5 “core actions”:

could readily and naturally revert to susceptibility in the absence of selective pressure shows tremendous potential for the fight against antibiotic resistance. Senior author, Mario Feldman, stated “This knowledge could lead to more effective treatments and better strategies for preventing the development of superbugs”. Read more here.

 Slow the development of resistant bacteria and prevent the spread of resistant infections  Strengthen National One-Health Surveillance efforts to combat resistance  Advance development and use of rapid and innovative diagnostic tests for identification and characterization of resistant bacteria

Common antacid shows promise in combatting multidrug-resistant tuberculosis

 Accelerate basic and applied research and development

In 2013, tuberculosis infection (caused by Mycobacterium

 Improve international collaboration and capacities for

tuberculosis) resulted in 9 million new infections and 1.5 mil-

antibiotic resistance prevention, surveillance, control, and

lion deaths globally.

antibiotic research and development

Second only to AIDS as the greatest

cause of global mortality, TB persists widely due to its multidrug resistance.

New drug development is very costly, in-

volving lengthy clinical trials, which has prompted scientists at the Ecole Polytechnique Federale de Lausanne to adopt an alternative strategy.

for new antibiotics, other therapeutics, and vaccines

The plan was unveiled as a result of the White House Forum on Antibiotic Stewardship held in early June. The CDC’s initiative is part of a wider national strategy that aims to improve the capacity of states to respond to, track, and prevent antibiotic misuse and decrease resistance. Visit the CDC website for

Using robotized, high-through-put assays, the scientists

more information.

screened previously approved chemicals for a possible solution and identified lansoprazole as a potential anti-TB drug. Also known as Prevacid® commercially, lansoprazole is an over-the -counter antacid found to kill the pathogen after the drug had been converted into a sulfur-containing metabolite by human lung cells. Further tests against a wide range of bacteria showed that the antacid was highly selective for M. tuberculosis. This fact, in combination with its safety record and global accessibility, makes lansoprazole a highly attractive candidate for combatting the global scourge of TB. Read the paper published in Nature Communications.

New susceptibility testing paradigm offers hope for more effective antibiotics Using a novel approach to test for antimicrobial susceptibility, researchers at the University of California Santa Barbara have uncovered the possible reason why some bacteria test "susceptible" in standard laboratory tests, but fail to respond to treatment in patients. Conventional antimicrobial susceptibility assays are performed in a standard test medium (Mueller -Hinton) with a pH of 7.2. medium

which

more

In experiments with a culture

closely

resembles

intracellular

Resistance in the News The APUA Newsletter Vol. 33. No. 2 • © 2015 APUA • 15

level resistance to two last-resort antibiotics (polymixin and

UK study reveals poor comprehension of antibiotic resistance issue

colistin), whereas it tested susceptible to these drugs in the

In an interview with BBC Radio, UK Chief Medical Officer,

standard media. Moreover, the strain could reverse from sus-

Dame Sally Davies, made the bold statement that “Modern

ceptible to resistant when transferred between the two media—

medicine, as we know it – if we don’t halt the rise of re-

a trait called TIVAR, or transient in vivo antibiotic resistance.

sistance – will be finished.” She spoke in response to a recent

Similar results were obtained with Y ersinia pseudotuberculosis,

report published by the Wellcome Trust (Exploring the con-

a gram-negative extracellular pathogen.

sumer perspective on antimicrobial resistance) which re-

conditions (an acidic pH of 5.2), Salmonella expressed high-

Lead researcher, Michael Mahan, noted a need for "lab drug sensitivity testing to incorporate media that mimic the specific biochemical environments that trigger resistance in the body."

If the millions of chemicals held in pharmaceutical

libraries were rescreened using different media, it could open up a world of more effective compounds for tackling the antibiotic resistance problem.

vealed that public understanding of resistance is very low in the UK. The researchers found that most study participants wrongly believed that resistance was caused by their bodies growing immune to antibiotics, rather than being caused by antibiotic-resistant bacteria. Another popular misconception was the fact that individuals thought because they didn’t misuse/abuse antibiotics, resistance would not be a problem for them.

16 • The APUA Newsletter Vol. 33. No. 2 • © 2015 APUA • Resistance in the News

Clearly, such erroneous thinking at the population level is an indicator of the lack of awareness of what resistance is and the factors that contribute to it. Without a targeted campaign of raising the public awareness and providing general practitioners the tools to properly educate their patients, resistance will continue to rise. Currently, around 25,000 people across Europe die due to infections caused by antibiotic-resistant bacteria. Experts have projected that this number will increase drastically if the trend of rising resistance is not curbed and reversed.

Hospital-acquired infections (HAIs) caused by antibioticresistant bacteria, including Clostridium difficile, continue to plague U.S. hospitals, with limited options for effective treatments. However, as announced in CDC’s latest V ital Signs post, a modelling study involving actual healthcare facilities reveals hope for interrupting the spread of HAIs if coordinated approaches between health facilities are employed. Data from the agency’s National Healthcare Safety Network and Emerging Infections Program were analyzed to project the number of HAIs, both with and without concerted intervention methods. Results showed that immediate nationwide infection control and antibiotic stewardship efforts could avert an estimated 619,000 HAIs (CRE, MDR Pseudomonas aeruginosa, MRSA and C. difficile) over a 5-year time period. Compared to stand-alone interventions, a coordinated reagainst

carbapenem-resistant

October 5-7, 2015: 4th International Conference on Clinical Microbiology and Microbial Genomics. Theme: Analyzing the Innovation & Future Trends in Clinical Microbiology. Philadelphia, PA, USA October 7-11, 2015: ID Week. A joint collaboration with the Infectious Diseases Society of America (IDSA), the Society for Healthcare Epidemiology of America (SHEA), the HIV Medicine Association (HIVMA) and the Pediatric Infectious Diseases Society (PIDS). San Diego, CA, USA October 13-16, 2015: 14th International Conference on the Chemistry of Antibiotics and other Bioactive Compounds (ICCA). Galveston Island, Texas, USA

CDC reveals encouraging outcome for integrated stewardship intervention

sponse

Upcoming Events

Enterobacteriaceae

(CRE) would result in a 74% reduction in acquisitions over 5 years in a 10-facility model, and a 55% reduction over 15 years in a 102-facility model.

November 3-5, 2015: The 5th annual antibiotic symposium of the National Institute for Animal Agriculture (NIAA). There: Antibiotic Stewardship: From Metrics to Management. Atlanta, GA, USA November 16-22, 2015: WHO’s first World Antibiotic Awareness Week U.S. CDC’s Get Smart About A ntibiotics W eek November 18, 2015: European CDC’s Antibiotic A wareness Day November 26-29, 2015: 15th Annual Asia-Pacific Congress of Clinical Microbiology and Infection (15th APCCMI). Kuala Lumpur, Malaysia February 25-27, 2016: Australian Society for Antimicrobials 17th Annual Scientific Meeting (Antimicrobials 2016). Melbourne, Australia April 9-12, 2016: 26th European Congress of Clinical Microbiology and Infections Diseases (ECCMID). Istanbul, Turkey June 11-13, 2016: Association for Professionals in Infection Control and Epidemiology (APIC) Annual Conference. Charlotte, N. Carolina, USA June 16-20, 2016: ASM Microbe 2016, combining meetings of the American Society for Microbiology (ASM) and the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Boston, MA, USA October 3-5, 2016: 2nd World Congress and Exhibition on Antibiotics (Antibiotics 2016). London, UK

http://ecdc.europa.eu/en/EAAD/Pages/Home.aspx

October 24-26, 2016: 5th International Conference on Clinical Microbiology and Microbial Genomics. Theme: Continuing the Effective Innovations in World’s Microbial Environment. Rome, Italy

Resistance in the News • The APUA Newsletter Vol. 33. No. 2 • © 2015 APUA • 17

Publications of Interest The complete brief can be accessed here.

PEW reveals findings on antibiotic development In late July, The Pew Charitable Trusts issued a brief on the

For more information on novel approaches to drug development, see the article by Kim Lewis in the spring 2015 issue of the APUA Newsletter (Vol 33, No 1).

research and development of antibiotics: Tracking the Pipeline of Antibiotics in Development. With antibiotic resistance on new drugs and innovative pathways to get this medicine to the

UK releases One Health Report: Joint report on human and animal antibiotic use, sales and resistance, 2013

patients who need it most.” Unfortunately, new drug

Acknowledging the need for a “One Health” approach to the

development requires extensive research, is cost-intensive, and

antibiotic resistance problem, Public Health England recently

requires years. It is estimated that only 1 out of 5 drugs that

published a report on the current state of antibiotic resistance

reach initial testing phase in humans achieves approval from

in the UK. It details the quantities of antibiotics used in

the

human health and animal welfare with the aims of:

the rise globally, it is imperative to have a “robust pipeline of

Food

and

Drug

Administration.

As

such,

the

pharmaceutical industry has been wary of investing in antibiotic development in recent decades.

 Encouraging further collaboration between the human and animal sectors;

Pew has assessed drugs that are currently in clinical

 Identifying the emerging and current antibiotic resistance

development and reported the following findings:

threats in three key bacteria in both humans and animals

 36 antibiotics are currently in development; 8 are in phase

 Identifying differences in surveillance methodology and

1 clinical trials, 20 in phase 2, and 8 in phase 3 (~60% of

data gaps that limit our ability to compare trends between

phase-3 drugs receive approval). (View table.)

the two fields, both within the UK and across Europe;

 At least 11 of the antibiotics have the potential to treat the ESKAPE

pathogens

(Enterococcus

Staphylococcus

aureus,

Klebsiella

Acinetobacter,

Pseudomonas

 Evaluating available data from humans and animals side by side and beginning assessment of the relationship

faecium,

between antibiotic sales, use and resistance across the

pneumoniae,

aeruginosa,

and

Enterobacter). If approved, 16 or more antibiotics could

two sectors;  Developing recommendations to improve the surveillance of antibiotic use and resistance in humans and

address CDC’s “urgent threat” pathogens (resistant N. gonorrhoeae,

C.

difficile,

and

The report highlights the fact that data collection across the

Enterobacteriaceae).  At least 2 antibiotics in early development attack bacteria in

novel

ways

by sidestepping

animals.

carbapenem-resistant

current

resistance

mechanisms. Others attack traditional targets with new chemical compounds.

country varies so markedly that it becomes impossible to make meaningful comparisons. This underscores the need for greater collaboration between human and animal health sectors in order to properly tackle antimicrobial resistance. The report identified Escherichia coli, Campylobacter, and

 Out of 31 companies with antibiotics in development, only

Salmonella as the top problematic bacteria for both human

5 rank among the top 50 pharmaceutical companies by

and animal health, and proffers ten recommendations for

sales. Three-quarters of new antibiotics are being

governmental action. A future report will provide update on

developed by small companies, of which ~40% are “pre-

progress.

revenue.”

Read the full report here.

18 • The APUA Newsletter Vol. 33. No. 2 • © 2015 APUA • Publications of Interest

Special journal edition focuses on global collaboration to address antimicrobial resistance

framework, the authors modeled a ‘behavioral analysis,’ which identified key behaviors and drivers that can become a focus for change.

The Journal of Law, Medicine & Ethics has published a special summer volume titled Antibiotic Resistance (co-guest edited by Steven J. Hoffman and Kevin Outterson), which focuses on how a global collaborative effort can address the urgent problem of increasing antimicrobial resistance. Specifically, it features a dozen articles in which the various authors issue a call for a general international consensus on antibiotic policy and “argue that such an agreement should address access, surveillance, prevention, infection control, the

The report considers 15 intervention opportunities as follows—dividing them into those that are achievable within different time frames: Short-term  Feedback on prescribing behaviors  Online pledges for parents  Improving the TARGET antibiotic leaflet* Medium-term

needs of the under-served, accountability, and which forums,

 Substitution of antibiotic therapy

such as the WHO, can help facilitate this policy”.

 Reducing patient appointments for self-limiting

In

producing this volume the editors state that “Our real

infections at GPs

innovation here is having taken a scientific approach to global

 Advising patients on their antimicrobial usage

strategy whereby we drew upon a range of disciplines to

 Adding friction to prescribing

systematically assess how instruments, institutions and

 Guideline implementation and decision support

initiatives could be designed to foster collective action on

 Making back-up prescribing the default for respiratory infections

ABR and maximize impact.”

 Improving the presentation of the TARGET clinical

This edition is the first of its kind for the Journal and is

guideline

available online only.

 Recording GP decision-making

For more on this topic, see the following:

 Design-led hospital prescription charts Long-term

Repairing the broken market for antibiotic innovation by K Outterson, JH Powers, GW Daniel & MB McClellan. Health

 Making antibiotic packaging salient

Affairs 2015. 34: 277-285. http://content.healthaffairs.org/

 Presenting resistance as a societal threat

content/34/2/277.full.html

 Increasing the cost of antimicrobials

UK report summarizes contribution of behavioral science to antibiotic stewardship

*A component of the Royal College of General Practitioners’ TARGET Antibiotics Toolkit; TARGET = Treat Antibiotics Responsibly, Guidance, Education, Tools

In a Feb. 2015 report titled Behaviour change and antibiotic prescribing in healthcare settings: literature review and behavioural analysis, Public Health England and the Department of Health issued strong support for using behavioral science to address the problem of high rates of antibiotic prescribing. The report reviews and summarizes the available evidence on behaviors that drive resistance— analyzing perspectives from patient use, prescribers, and primary and secondary care.

Using a theoretical domains Publications of Interest • The APUA Newsletter Vol. 33. No. 2 • © 2015 APUA • 19

“Preserving the Power of Antibiotics” ® About us Antibiotics are humanity's key defense against disease-causing microbes. The growing prevalence of antibiotic resistance threatens a future where these drugs can no longer cure infections and killer epidemics run rampant. The Alliance for the Prudent Use of Antibiotics (APUA) has been the leading global non-governmental organization fighting to preserve the effectiveness of antimicrobial drugs since 1981. With affiliated chapters in more than 65 countries, including 33 in the developing world, we conduct research, education and advocacy programs to control antibiotic resistance and ensure access to effective antibiotics for current and future generations. Our global network of infectious disease experts supports country-based activities to control and monitor antibiotic resistance tailored to local needs and customs. The APUA network facilitates the exchange of objective, up-to-date scientific and clinical information among scientists, health care providers, consumers and policy makers worldwide.

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