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

Fall 2015

Volume 33, No. 2

Strategies for improving antimicrobial stewardship

Visit our website Support our work

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

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, 4-

epioxytetracycline, 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.

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

Chief Executives Stuart B. Levy, President

Thomas F. O’Brien, Vice President

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

Advisory Board (cont) 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 Project Partnerships: The Bill and Melinda Gates Foundation

The Pew Charitable Trusts

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(PAHO)

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ment (USAID)

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tion (CDC)

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ion Agency

Supporting Chapters: APUA—Abu Dhabi

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(APUA-Australia)

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therapy (APUA-UK)

APUA gratefully acknowledges unrestrict-

ed grants from corporate sponsors:

Leadership Level ($20,000+) Clorox Healthcare

bioMérieux

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Da Volterra

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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

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Introduction to this issue

This issue of the APUA Newsletter touches on two diverse

topics related to antibiotic use, both environmentally and

clinically. The topic of antibiotics and their impacts on the

aquaculture industry is addressed by Caruffo and Navarrete.

This issue has long festered in the shadows cast by the

enormous focus placed on antibiotic growth promotion use in

food animal farms. The burgeoning fish farming industry—

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

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

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

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

raised. With its frequently unregulated and questionable

antimicrobial use practices, the industry bears closer scrutiny

as a potential contributor to the escalating antibiotic

resistance problem.

Our second article discusses the status and future of

aerosolized antibiotics – a method of delivery that was first

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

penicillin G, ticarcillin, ceftazidine and carbenicillin, were

largely abandoned due to the severe side effect of

bronchospasm and other poor outcomes that may have been

due to shortcomings in methodology. The rise of ventilator-

associated pneumonia (pneumonia in a patient who has been

mechanically ventilated for at least 48h) due to multidrug

resistant pathogens such as Acinetobacter baunannii and

Pseudomonas aeruginosa and the need for targeted

antimicrobial therapy have prompted a reexamination of this

method for antibiotic delivery. Today - both jet and ultrasonic

nebulizers effectively deliver therapeutic levels of drug in

>90% of patients with minimal systemic dispersion. The

article by Walson discusses current practices and the

continuing need for clinical trials to resolve some ongoing

issues with the use of this mode of therapy.

by Bonnie Marshall (APUA staff)

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

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

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

simulate important evolutionarily conserved responses in the

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

Proteobacteria, Firmicutes, Bacteroidetes, Fusobacteria,

Actinobacteria, Clostridia, Bacilli, and Verrucomicrobia.

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

crobiota, which include epithelial proliferation, the promotion

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

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

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

es.13 Consequently, the eventual modification of the microbial

composition by antibiotic treatment could lead to alteration in

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 concen-

tration, as well as the fish species involved. Oxolinic acid

(OA), oxytetracycline (OTC) and sulphafurazole reportedly

cause an increase in bacterial densities throughout the diges-

tive tract of rainbow trout (Salmo gairdneri Richardson).24 In

contrast, erythromycin and penicillin G both produced a rap-

id 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 popula-

tion.26 This reduction was greater in bacteria from digesta

when compared to those associated with the mucosa—with

The aquaculture industry provides high quality protein for bil-

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

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

centage of wild fish stocks are experiencing depletion, nearly

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

culture.2 Antibiotics in aquaculture have been used primarily as

therapeutic and prophylactic agents, with varying regulations

depending on the country, which complicates the determina-

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

tions between countries, with use ranging from an estimated 1

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

ton in Vietnam.3 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 in-

gested, 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 chemi-

cals, with a large impact on biodiversity and selection of re-

sistant 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 concen-

trations are lower and diversity is less broad than in the mam-

malian intestinal microbiota, the gut microbiota of fish

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

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

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

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

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

the total intestinal counts in hybrid tilapia.28

Studies show that antibiotics can also alter the composition of

the gut microbiota of fish, triggering a reduction in bacterial

diversity and enabling the proliferation of opportunistic or

resistant bacteria. The administration of three dosages of OA

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

that intestinal Aeromonas remained susceptible to OA.25 In

contrast, OA stimulated the proliferation of OA-resistant Aer-

omonas 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

themselves.25

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

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

teria from the intestines of healthy juvenile Atlantic salmon

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

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

fish remained diverse (predominantly Pseudomonas, Acineto-

bacter, Bacillus, Flavobacterium, Psychrobacter, and Bre-

vundimonas/Caulobacter/Mycoplana) diversity in the OTC-

treated fish was markedly reduced and only the opportunistic

pathogens Aeromonas veronii bv. sobria and A. salmonicida

were isolated.27 Antibiotic treatment markedly increased the

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

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

pectively. The most frequent resistant determinants identified

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

Following 8 weeks of treatment with the growth promoters fla-

vomycin (20 mg/kg) and florfenicol (20 mg/kg), and the combi-

nation of the two (10+10 mg/kg), bacterial diversity of the au-

tochthonous intestinal microbiota of hybrid tilapia was affected

as demonstrated by changes in band presence and intensity in

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

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

significant reduction in bacterial richness, reflected by a re-

duced number of DGGE bands.29 The administration of this

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

carvacrol (oregano).

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

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.

Alternative treatments to antibiotics

Antibiotic resistance among bacterial pathogens and concerns

over the extensive use of antibiotics in animal production, in-

cluding aquaculture, have gained global interest. This is reflect-

ed 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 con-

trol bacterial infections are needed.

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 investi-

gated, while other methods (e.g., antimicrobial peptides, bacteri-

ocins, 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

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 Post-

2015 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.

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

ment. Available at www.seafoodwatch.org/-/m/sfw/pdf/reports/

mba_seafoodwatch_farmedsalmonsummary.pdf. Accessed Septem-

ber 15, 2015.

6. Cabello F, Godfrey H, Tomova A, et al Antimicrobial use in aqua-

culture re-examined: its relevance to antimicrobial resistance and to

animal and human health. Environ Microbiol. 2013; 15: 1917-

1942.

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 biopro-

cessed 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 salm-

on (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. Aqua-

culture. 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 intesti-

nal 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 differentia-

tion. 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 β-

Lactams, 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 imbal-

ances in gut microbiota aggravates cholesterol accumula-

tion 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 anti-

biotic 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 com-

pounds 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 antibiotic-

resistant 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 microbio-

ta 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 treat-

ment reduces bacterial diversity of intestinal microbiota of Atlan-

tic salmon. J Aquat Anim Health. 2008; 20: 177-183.

28. He S, Zhou Z, Liu Y, et al. Effects of the antibiotic growth pro-

moters flavomycin and florfenicol on the autochthonous intesti-

nal 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 senega-

lensis 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 re-

sistance 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 Vibrio 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 bacte-

rial disease resistance of transgenic channel catfish Ic-

taulurus punctatus possessing cecropin genes. Mar Bio-

technol. 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 rain-

bow trout (Oncorhynchus mykiss) immune response by the hu-

man alpha defensin 1, HNP1. Fish Shellfish Immunol. 2008; 24:

102-112.

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

Caruffo & Navarrete references continued on p. 13

Update

Nebulized antimicrobial drug delivery

Philip D. Walson, MD, Visiting Professor, Department of

Clinical Pharmacology, University Medical Center, Goettingen,

Germany

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

the patient.7 There are major differences in the performance

of different methods and devices used to generate aerosols

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

factors. There are also drug, concentration and formulation

factors that affect the efficiency of drug delivery to the

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

administered drug is swallowed versus inhaled, as well as

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, drug-

specific effects on the efficacy of inhaled drug delivery.

Experimental evidence in rodents shows that

fluoroquinolones are more effective when aerosolized

because they achieve high pulmonary fluid concentrations.9

However, other authors have questioned whether there is

any biopharmaceutical advantage to nebulization versus

intravenous use.10 These authors claimed that the several-

fold increases they observed in rodent pulmonary fluid-to-

plasma concentration ratios of three fluoroquinolones were

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

pulmonary efflux transporters that concentrate

fluoroquinolones in pulmonary fluid. Clearly more studies

are needed to establish, in humans, which nebulized drugs

are more effective and why.

Research needed

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

Antimicrobial drugs are usually given by either oral or

intravenous routes. Increasing interest has been shown in the

inhaled route of administration using either drug powders or

aerosols to treat a number of diseases including pneumonia and

sinusitis, based on the possibility of achieving higher

concentrations at the site of infection with less systemic drug

exposure and less toxicity.1

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.

Aerosolized antibiotics: uses and efficacy

Many antibiotics are routinely given as aerosols to patients

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

tobramycin and amikacin), colistin and aztreonam. A number

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

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

These and other antibiotics are being given to patients with

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

with multidrug-resistant bacterial infections when the minimal

inhibitory concentrations exceed those that can be safely

achieved intravenously.6 Aerosolized antibiotics are likewise

being used in patients with limited IV access and inability to

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

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

aminoglycoside concentrations in CF patients who use face

mask-aerosolized antibiotics because their fingers are

contaminated with the aerosolized drug.11 While less of a

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

potentially, to those who handle the patient’s bodily fluids,

stool, urine and waste. The fact that higher concentrations and

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

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

administer drugs or amounts that cannot be given safely by oral

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

associated with inhalation therapy, including environmental

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 manu-

factures aerosol devices for medication delivery.

References:

1. Hagerman JK, Hancock KE, Klepser ME. Aerosolised

antibiotics: a critical appraisal of their use. Expert Opin.

Drug Deliv. 2006;3:71–86.

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

10 • The APUA Newsletter Vol. 33. No. 2 • © 2015 APUA • APUA HQ in Action

APUA Headquarters in Action

APUA staff attend Longitude Prize

informational meeting

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

prize fund which aims to conserve antibiotics for future

generations and revolutionize the delivery of global

healthcare. Prize administrators, including Professor of Health

Law Kevin Outterson of Boston University School of Law,

described the qualities judges sought in entries at a Harvard

Business School promotional meeting. APUA’s Dr. Thomas

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

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

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

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

longitudeprize.org Entries are still being accepted.

Clorox partners with APUA

On September 3rd, Clorox Healthcare issued a press release

announcing its new partnership with APUA to raise awareness

on the link between antimicrobial stewardship, environmental

hygiene and infection control practices.

“Ours is a natural alliance because strengthening health

systems and clinical practice by cleaning, disinfection and

process compliance reduces or prevents transmission of

resistant bacteria. There are strategies that APUA champions

globally and Clorox Healthcare helps realize,” said Stuart B.

Levy, MD, President of APUA.

“APUA and Clorox Healthcare will work together to raise

awareness of this important issue and strengthen educational

programs that inform best practices in infection prevention and

antibiotic stewardship,” said Rosie Lyles, MD, MHA, MLSc,

Head of Clinical Affairs for Clorox Healthcare.

Transitions

APUA extends its deepest thanks to Dr. Gordon W.

Grundy as he completes 12 years of outstanding

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

Board we wish him well in all his future endeavors.

Thank you Dr. Grundy!

APUA supports multiple legislative initiatives

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

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

Antibiotic and Diagnostic Innovation (READI) Act" would

provide a tax incentive for qualifying manufacturers to increase

clinical testing of antibiotic and antifungal drugs and rapid

diagnostics for infectious diseases. Signed by over 40

supporting organizations, the letter emphasizes the need for

new antibiotic development and the need to provide incentives

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

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.

APUA has joined with Pew Charitable Trusts and other

interested organizations in signing on to a letter in support of

the Centers for Medicare and Medicaid (CMS) proposed rule

(Federal Register CMS-3260-P) that would make stewardship

programs a condition of participation for long-term care (LTC)

facilities. Because long-term care residents are often prescribed

antibiotics, LTC facilities should implement antibiotic

stewardship programs to monitor and ensure appropriate

antibiotic use.

APUA-Bulgaria chapter specialists in Clinical Microbiology,

Epidemiology and Infectious Diseases organized and/or

participated in the following scientific events during the first

half of 2015:

The scientific conference Particularly Dangerous

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

2015, (organized by the National Center for Infectious and

Parasitic Diseases);

The 8th 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

Tularemia were recorded in Bulgaria during the past 10 years,

with seven new cases appearing since the beginning of 2015;

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

participants in scientific projects and forums dedicated to

preventing antimicrobial resistance. European Antibiotic Day is

traditionally celebrated on November 18 and Medical

University professors participate with specialized lectures and

exercises on the issue.

In conclusion, Bulgar-

ian microbiologists, epi-

demiologists and in-

fectious diseases spec-

ialists share concern

about the problem of

antimicrobial resistance

and work to prevent

further development

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

International Chapter Updates

Chapter Spotlight: APUA-Bulgaria

Founded: 1998

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) Infec-

tious Diseases (ESCiD), International Society of Chemother-

apy (ISC) and others.

Membership: 105

Bulgaria

Prof. Encho Savov

President, APUA-Bulgaria

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

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

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

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

Milanova M, Lesseva M. Antibiotic policies in cardiology.

Cardio-vascular Dis. 64, 2013, 1: 30-35

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

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 &

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 Gram-

positive clinical isolates. Trakia J of Sciences, 2013, 4: 334-

337

Savov E, Trifonova A, Gergova I, Borissova M, Kioseva E,

Todorova I. Antibiotic resistance, a world challenge.

Preventive Med. 2, 2014, 7: 3-8

Members of the APUA-Bulgaria delegation

APUA – South Africa

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

South Africa published its Antimicrobial Resistance (AMR)

National Strategy Framework 2014-2024 in October 2014.

This framework provides “a structure for managing AMR to

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

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 communication and

information campaign. 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.

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

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 Vibrio

harveyi bacteriophage with a potential for biocontrol of lumi-

nous vibriosis in hatchery environments. Aquaculture. 2006;

255: 117-124.

38. Stenholm AR, Dalsgaard I, Middelboe M. Isolation and character-

ization of bacteriophages infecting the fish pathogen Flavobacte-

rium psychrophilum. Appl Environ Microbiol. 2008; 74: 4070-

4078.

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: 680-

685.

40. Liu Y, De Schryver P, Van Delsen B, et al. PHB-degrading bac-

teria 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 weap-

ons 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 aquacul-

ture: 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 Mi-

crobiol. 28: doi: 10.1111/jam.12886.

46. Standen BT, Rodiles A, Peggs DL, et al. Modulation of the intes-

tinal microbiota and morphology of tilapia, Oreochromis nilot-

icus, 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 vul-

garis essential oil on intestinal bacterial microbiota of rainbow

trout, Oncorhynchus mykiss (Walbaum) and bacterial isolates.

Aquacult Res. 2010. 41: 667-678.

Coming Soon!

Garlic compound shows promise in fight

against multidrug-resistant pathogens

Scientists at the Birla Institute of Technology and Sciences in

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

ties that are effective in fighting multi-drug resistant bacteria

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

the chemical allicin, which gives garlic its signature scent and

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

herb’s antibiotic properties.

Published in Pertanika Journal of Tropical Agricultural Sci-

ence, 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

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

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

showed susceptibility to the chemical.

An earlier article in PlosOne (Garlic revisited: antimicrobial

activity of allicin-containing garlic extracts against Burkhold-

eria cepaia complex) suggests that allicin has potential as an

adjunct to existing antibiotics in the treatment of the intrinsi-

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 inves-

tigate a crucial factor—whether oral administration or injec-

tion provides the most effective delivery.

“Weaponized” Acinetobacter demonstrates

self-limiting resistance

In a recent PNAS study, researchers at the Washington Uni-

versity School of Medicine in St. Louis suggest that drug-

resistant bacteria can be self-limiting. The researchers focused

on multidrug-resistant Acinetobacter baumannii, a leading

hospital-acquired bacterium that also survives disinfectants,

Resistance in the News

News and Publications of Note • The APUA Newsletter Vol. 32. No. 1 • © 2014 APUA • 14

Point-of-care CRP test shows promise for re-

ducing antibiotic prescriptions

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

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

protein could potentially reduce the number of antibiotic pre-

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

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

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

prick blood sample with results available in a few minutes to

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”.

The report goes on to make recommendations for policymak-

ers, commissioners, and health professionals including:

Routine use of POC CRP testing by health professionals

and its integration into patient consultation;

Recognize the POC CRP testing could help clinical com-

missioning groups attain the Quality Premium and meet

the NHS quality agenda;

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 guide-

lines that support accurate differential diagnosis for respir-

atory tract infections.

For a summary of APUA’s summit on point-of-care rapid

diagnostics including CRP, see APUA Newsletter Vol 32(2),

2014, p20 and the subsequent publication: Improving outpa-

tient 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.

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

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 com-

prehensive response to fighting resistance.

The response strategy, aptly named the Antibiotic Resistance

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

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

Accelerate basic and applied research and development

for new antibiotics, other therapeutics, and vaccines

Improve international collaboration and capacities for

antibiotic resistance prevention, surveillance, control, and

antibiotic research and development

The plan was unveiled as a result of the White House Forum

on Antibiotic Stewardship held in early June. The CDC’s initi-

ative is part of a wider national strategy that aims to improve

the capacity of states to respond to, track, and prevent antibi-

otic misuse and decrease resistance. Visit the CDC website for

more information.

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 suscepti-

bility assays are performed in a standard test medium (Mueller

-Hinton) with a pH of 7.2. In experiments with a culture

medium which more closely resembles intracellular

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

making it very difficult to treat. This organism carries a toxic

type VI secretion system (T6SS) that acts as a survival strate-

gy 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.

Further studies on samples from outbreaks across the globe

showed the same pattern. The discovery that such superbugs

could readily and naturally revert to susceptibility in the ab-

sence of selective pressure shows tremendous potential for the

fight against antibiotic resistance. Senior author, Mario Feld-

man, stated “This knowledge could lead to more effective

treatments and better strategies for preventing the development

of superbugs”. Read more here.

Common antacid shows promise in combat-ting multidrug-resistant tuberculosis

In 2013, tuberculosis infection (caused by Mycobacterium

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

lion deaths globally. Second only to AIDS as the greatest

cause of global mortality, TB persists widely due to its multi-

drug 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.

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

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. tuberculo-

sis. 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.

UK study reveals poor comprehension of

antibiotic resistance issue

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

Dame Sally Davies, made the bold statement that “Modern

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

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

report published by the Wellcome Trust (Exploring the con-

sumer perspective on antimicrobial resistance) which re-

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 mis-

use/abuse antibiotics, resistance would not be a problem for

them.

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

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

level resistance to two last-resort antibiotics (polymixin and

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

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

ceptible to resistant when transferred between the two media—

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

Similar results were obtained with Y ersinia pseudotuberculosis,

a gram-negative extracellular pathogen.

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 antibi-

otic resistance problem.

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

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 practi-

tioners 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 in-

crease drastically if the trend of rising resistance is not curbed

and reversed.

CDC reveals encouraging outcome for

integrated stewardship intervention

Hospital-acquired infections (HAIs) caused by antibiotic-

resistant bacteria, including Clostridium difficile, continue to

plague U.S. hospitals, with limited options for effective treat-

ments. However, as announced in CDC’s latest Vital Signs

post, a modelling study involving actual healthcare facilities

reveals hope for interrupting the spread of HAIs if coordinat-

ed 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 inter-

vention 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 re-

sponse against carbapenem-resistant 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.

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 Epide-

miology 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

November 3-5, 2015:

The 5th annual antibiotic symposium of the National Institute

for Animal Agriculture (NIAA). There: Antibiotic Steward-

ship: 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 Antibiotics Week

November 18, 2015:

European CDC’s Antibiotic Awareness 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 Infec-

tions Diseases (ECCMID). Istanbul, Turkey

June 11-13, 2016:

Association for Professionals in Infection Control and Epide-

miology (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 Confer-

ence on Antimicrobial Agents and Chemotherapy (ICAAC).

Boston, MA, USA

October 3-5, 2016:

2nd World Congress and Exhibition on Antibiotics (Antibiotics

2016). London, UK

October 24-26, 2016:

5th International Conference on Clinical Microbiology and

Microbial Genomics. Theme: Continuing the Effective Inno-

vations in World’s Microbial Environment. Rome, Italy

Upcoming Events

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

PEW reveals findings on antibiotic

development

In late July, The Pew Charitable Trusts issued a brief on the

research and development of antibiotics: Tracking the Pipeline

of Antibiotics in Development. With antibiotic resistance on

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

new drugs and innovative pathways to get this medicine to the

patients who need it most.” Unfortunately, new drug

development requires extensive research, is cost-intensive, and

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

reach initial testing phase in humans achieves approval from

the Food and Drug Administration. As such, the

pharmaceutical industry has been wary of investing in

antibiotic development in recent decades.

Pew has assessed drugs that are currently in clinical

development and reported the following findings:

36 antibiotics are currently in development; 8 are in phase

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

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

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

ESKAPE pathogens (Enterococcus faecium,

Staphylococcus aureus, Klebsiella pneumoniae,

Acinetobacter, Pseudomonas aeruginosa, and

Enterobacter). If approved, 16 or more antibiotics could

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

gonorrhoeae, C. difficile, and carbapenem-resistant

Enterobacteriaceae).

At least 2 antibiotics in early development attack bacteria

in novel ways by sidestepping current resistance

mechanisms. Others attack traditional targets with new

chemical compounds.

Out of 31 companies with antibiotics in development, only

5 rank among the top 50 pharmaceutical companies by

sales. Three-quarters of new antibiotics are being

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

revenue.”

The complete brief can be accessed here.

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).

UK releases One Health Report: Joint report

on human and animal antibiotic use, sales and

resistance, 2013

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

antibiotic resistance problem, Public Health England recently

published a report on the current state of antibiotic resistance

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

human health and animal welfare with the aims of:

Encouraging further collaboration between the human

and animal sectors;

Identifying the emerging and current antibiotic resistance

threats in three key bacteria in both humans and animals

Identifying differences in surveillance methodology and

data gaps that limit our ability to compare trends between

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

Evaluating available data from humans and animals side

by side and beginning assessment of the relationship

between antibiotic sales, use and resistance across the

two sectors;

Developing recommendations to improve the sur-

veillance of antibiotic use and resistance in humans and

animals.

The report highlights the fact that data collection across the

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

Salmonella as the top problematic bacteria for both human

and animal health, and proffers ten recommendations for

governmental action. A future report will provide update on

progress.

Read the full report here.

Publications of Interest

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

Special journal edition focuses on global

collaboration to address antimicrobial

resistance

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

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

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

producing this volume the editors state that “Our real

innovation here is having taken a scientific approach to global

strategy whereby we drew upon a range of disciplines to

systematically assess how instruments, institutions and

initiatives could be designed to foster collective action on

ABR and maximize impact.”

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

available online only.

For more on this topic, see the following:

Repairing the broken market for antibiotic innovation by K

Outterson, JH Powers, GW Daniel & MB McClellan. Health

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

content/34/2/277.full.html

UK report summarizes contribution of

behavioral science to antibiotic stewardship

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

framework, the authors modeled a ‘behavioral analysis,’

which identified key behaviors and drivers that can become a

focus for change.

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

Substitution of antibiotic therapy

Reducing patient appointments for self-limiting

infections at GPs

Advising patients on their antimicrobial usage

Adding friction to prescribing

Guideline implementation and decision support

Making back-up prescribing the default for respiratory

infections

Improving the presentation of the TARGET clinical

guideline

Recording GP decision-making

Design-led hospital prescription charts

Long-term

Making antibiotic packaging salient

Presenting resistance as a societal threat

Increasing the cost of antimicrobials

*A component of the Royal College of General Practitioners’

TARGET Antibiotics Toolkit; TARGET = Treat Antibiotics

Responsibly, Guidance, Education, Tools

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 Antibi-

otics (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 gen-

erations.

Our global network of infectious disease experts supports country-based activities to control and monitor antibiotic resistance tai-

lored to local needs and customs. The APUA network facilitates the exchange of objective, up-to-date scientific and clinical infor-

mation among scientists, health care providers, consumers and policy makers worldwide.

The APUA Newsletter has been published continuously three times per year since 1983.

Tel: 617-636-0966 • Email: apua@tufts.edu • Web: www.apua.org

APUA global chapter network

of local resources & expertise

136 Harrison Ave, M&V Suite 811, Boston, MA 02111

Phone: 617-636-0966 | Fax: 617-636-0458 | E-mail: apua@tufts.org

www.apua.org

20 • The APUA Newsletter Vol. 33. No. 2 • © 2015 APUA • About Us

“Preserving the Power of Antibiotics” ®