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
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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
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Stuart B. Levy, Newsletter Editor
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Otto Cars, Sweden
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Jose Ramiro Cruz, Guatemala
Julian Davies, Canada
Abdoulaye Djimde, Mali
Paul Farmer, Haiti
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Sherwood l. Gorbach, USA
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Jay A. Levy, USA
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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: [email protected] • 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: [email protected]
www.apua.org
20 • The APUA Newsletter Vol. 33. No. 2 • © 2015 APUA • About Us
“Preserving the Power of Antibiotics” ®
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