9 ASIAN

th ­

RTI FORUM
7 - 8 March 2015
Sheraton Saigon Hotel & Towers
Ho Chi Minh City, Vietnam

Antimicrobial Therapy in LRTIs-

Making the Appropriate Choices
Disclaimer
Below is indication of Avelox which already approved from BPOM Republic of Indonesia :
Avelox 400 mg film coated tablets are indicated for the treatment of adults (>18 years of age) for
the following bacterial infections:
• Acute exacerbations of chronics bronchitis
• Community acquired pneumonia
• Acute bacterial sinusitis ( adequately diagnosed)
• Complicated skin and skin structure infections who require initial parenteral theraphy;
followed by oral; in patients who are intolerance to alternative agents (especially penicillin
allergy), and when caised by organisms known to be susceptible to moxifloxacin.
• Complicated intra-abdominal infection due to polymicrobial infections in patients who are
intolerance to alternative agents; caused by organisms known to be susceptible to
moxifloxasin
• Mild to moderate pelvic inflammatory disease (i.e. infections of female upper genital tract,
including salpingitis and endomettritis), without an associated tubo-ovarian or pelvic
inflammatory disease but should be given in combination with another appropriate
antibacterial agent (e.g. cephalosporin) due to increasing moxifloxacin resistance of Neisseria
gonorrhoeae unless moxifloxacin-resistant Neisseria gonorrhoeae can be excluded.
Avelox 400 mg film coated tablets are indicated for the treatment of the above infections if they
are caused by bacteria susceptible to moxifloxacin.
Consideration should be given of official guidance on the appropriate use of antibacterial agents.
Avelox may only be used on prescription and under the constant supervision of doctor.
Avelox IV is only for patients that can not take oral administration or clinically proven have to taje
parenteral administration.
Avelox infusions 400 mg are indicated for the treatment of adults (. 18 years of age) for the
following bacterial infections:
• Avelox exacerbations of chronic bronchitis
• Community acquired pneumonia
• Acute bacterial sinusitis (adequately diagnosed)
• Complicated skin and skin structure infections who require initial parenteral therapy; followed
by oral; in patients who are intolerance to alternative agents (especially penicillin allergy), and
when caused by organisms known to be susceptible to moxifloxacin.
• Complicated intra-abdominal infections due to polymicrobial infections in patients who are
intolerance to alternative agents; caused by organisms known to be susceptible to
moxifloxacin.
Avelox infusions 400 mg are indicated for the treatment of the above infections if they are
caused by bacteria susceptible to moxifloxacin.
Consideration should be given of official guidance on the appropriate use of antibacterial agents.
Avelox may only be used on prescription and under the constant supervision of doctor.
9th Asian RTI Forum
7–8 March 2015
Sheraton Saigon Hotel & Towers, Ho Chi Minh City, Vietnam
Welcome and Introduction
Dear Colleagues
I would like to welcome you to the 9th Asian RTI Forum, where we will be focusing on the issues we
face in managing lower respiratory tract infections (LRTIs), and in particular the challenges posed
by the ever-present threat of antimicrobial resistance and the need to select the most appropriate
antibiotic therapies.
This year the RTI Forum focuses on best practice in the management of pneumonia in the community
and acute exacerbations of chronic obstructive pulmonary disease, as well as new advances in the
management of challenging LRTIs. Effective antimicrobial therapy is fundamental to the management
of respiratory infections, and we will examine the key methods and processes in this area. In addition,
we will give you an update on the use of biomarkers in clinical practice, and an insight into current
thinking on the effect of chronic respiratory disease on the normal flora of the lung.
Within the Asia Pacific region, increasing resistance to many antibiotic classes and the rising costs
of healthcare provision mean that we all need to consider the choice of antibiotics very carefully.
We have invited international speakers from across Asia, Europe and the USA, who will share their
insight and experience with us throughout the meeting.
We encourage you to actively participate throughout the meeting – we have a voting system during
the talks, as well as the opportunity to raise questions from the floor during the Q&A sessions. We
would also encourage you to interact with your colleagues during the scheduled breaks and discuss
the points raised in the meeting.
I am sure you will join me in thanking everyone who has worked hard to make this meeting possible.
I hope that you will find this 9th Asian RTI Forum both enjoyable and informative.
Yours Sincerely
Dr Le Thi Tuyet Lan Dr Tran Van Ngoc
Head of Respiratory Care Center Vice Dean of University of Medicine and Pharmacy – HCMC
University Medical Center Head of Respiratory Department – Cho Ray Hospital
Ho Chi Minh City, Vietnam Ho Chi Minh City, Vietnam
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Antimicrobial therapy in LRTIs – making the appropriate choices
9th Asian RTI Forum
7–8 March 2015
Sheraton Saigon Hotel & Towers, Ho Chi
Minh City, Vietnam

Day 1: 7 March 2015 Day 2: 8 March 2015

Time Title Presenter Time Title Presenter

13:00 Welcome and Introduction Chair: Le Thi Tuyet Lan (Vietnam) 08:30 Introduction (Review of Day 1) Chair: Tran Van Ngoc (Vietnam)
13:15 Welcome Bayer Representative
Session III: Facing Challenges in LRTIs Chair: Sanjay Sethi (USA)
Session I: Antibiotic Resistance Chair: Tobias Welte (Germany)
08:45 Managing CAP in an Area of Endemic TB Tobias Welte (Germany)
13:30 Emerging Trends in Resistance in Asia Bin Cao (China) 09:25 Gram-negative Pneumonia in the ICU Kuang-Yao Yang (Taiwan)
14:00 Antibiotic Stewardship Against Antimicrobial Christopher Lee (Malaysia) 10:05 Non-Cystic Fibrosis Bronchiectasis: Breaking the Kenneth Tsang (Hong Kong)
Resistance: Are We Winning or Losing? Vicious Cycle
14:30 Product Safety and Quality: Paul Tulkens (Belgium) 10:45 Looking to the Future: Building on the Bayer Martin Springsklee (Germany)
an Act of Social and Ethical Responsibility Heritage
(Discussion About Generic Antibiotics) 11:15 Break
15.00 Break 11:45 Case Presentations: CAP, AECOPD, Biomarkers Tobias Welte (Germany)
Sanjay Sethi (USA)
Session II: Evidence-Based Best Practice in LRTI Chair: John Hurst (UK) John Hurst (UK)
12:45 Closing
15:30 Antibiotics for CAP: from Clinical Trial to Practice Tobias Welte (Germany) 13:00 End
15:50 Antibiotics for AECOPD: Making the Right Choice Sanjay Sethi (USA)
16:10 Panel Discussion
16:30 Biomarkers in Practice: Making an Impact on John Hurst (UK)
Patient Management
17:10 Lung Microbiome and its Potential Role in COPD Sanjay Sethi (USA)
17:50 Closing remarks

4 5
Chairpersons
Le Thi Tuyet Lan
University Medical Center,
Ho Chi Minh City, Vietnam
Professor Le Thi Tuyet Lan is
currently head of the Respiratory
Care Center of the University
Medical Center in Ho Chi Minh
City (HCMC), Vietnam. Professor Le
Thi Tuyet Lan received his training
at the University of Medicine and
Pharmacy in HCMC, and obtained
his PhD from the Academy of
Medicine in the former Soviet
Union.
9th Asian RTI Forum
7–8 March 2015
Sheraton Saigon Hotel & Towers, Ho Chi
Minh City, Vietnam
6 7
Tran Van Ngoc
University of Medicine and Pharmacy,
Ho Chi Minh City, Vietnam
Dr Tran Van Ngoc is currently Vice-
Dean of the Department of Internal
Medicine within the University of
Medicine and Pharmacy, Ho Chi Minh
City (HCMC), Vietnam. Dr Tran Van
Ngoc has worked at the University
since 1998 in a lecturing, teaching
and managerial capacity while
simultaneously continuing to practice
medicine at Cho Ray Hospital, HCMC.
Abstract
Session I: Antibiotic Resistance
Chair/Moderator: Tobias Welte
Hannover University School of Medicine,
Hannover, Germany
Emerging Trends in Resistance in Asia
Bin Cao
Beijing Chao-Yang Hospital, Beijing, Republic of China
Professor Bin Cao is Director of the Department of Infectious Diseases and Clinical Microbiology,
Beijing Chao-Yang Hospital, Beijing Institute of Respiratory Medicine, Capital Medical University
in Beijing.
According to a systematic analysis for the Global Burden of Disease Study published in The Lancet
in 2014, lower respiratory tract infection is a major health problem. There is growing evidence of
an increasing proportion of community-acquired pneumonia (CAP) cases being caused by drug-
resistant bacteria in the past 10 years, both in adults and in children. The proportion of isolates
resistant to antimicrobials is increasing among Streptococcus pneumoniae, Staphylococcus
aureus and Mycoplasma pneumoniae, and treatment of pneumonia due to these pathogens can
be a challenge for clinicians.
Emerging resistance to macrolides and beta-lactams among S. pneumoniae isolates is concerning
because it can result in clinical treatment failure, as well as increased morbidity and mortality in
CAP patients. A report from The Asian Network for Surveillance of Resistant Pathogens (ANSORP)
showed that among nonmeningeal isolates, the prevalence rate of penicillin-nonsusceptible
pneumococci (MIC >4 mg/mL) was 4.6% and penicillin resistance (MIC >8 mg/mL) was 0.7%.
Resistance to erythromycin was very prevalent in the region (72.7%); the highest rates were
in China (96.4%) and Vietnam (80.7%). Multidrug resistance (MDR) was observed in 59.3% of
isolates from Asian countries.
Over the past decade, the epidemiology of methicillin-resistant Staphylococcus aureus (MRSA)
has evolved rapidly, with the spread of community-acquired MRSA (CA-MRSA) strains, which
have different genetic backgrounds to the healthcare-associated (HA) strains. CA-MRSA carries
smaller SCCmec elements than HA-MRSA, generally type IV and V. Several sequence types of
CA-MRSA have been described worldwide, and their prevalence varies widely from area to area.
USA300/ST8 has become the dominant clone in the USA, whereas the ST80 clone is prevalent
in Europe, ST59 in China, and ST93 in Australia. The incidence of paediatric invasive CA-MRSA
infection increased from 0 to 2.43 per 10,000 admissions in Chinese children between 2006
and 2011.
Since 2000, the prevalence of macrolide-resistant Mycoplasma pneumoniae (MRMP) has been
described with increasing incidence worldwide. MRMP has become widespread in East Asia,
with up to 90% of M. pneumoniae strains being resistant in China. Recent reports have also
documented the emergence of MRMP in the West, but with lower prevalence: 8.2% in the USA,
0.9–2.9% in Denmark, 3% in Germany, 10% in France and 32% in Israel.
The theme of the WHO World Health Day 2011 was antimicrobial resistance, with a slogan
entitled “Antimicrobial resistance: no action today, no cure tomorrow”. There have been strong
correlations between antibiotic abuse or misuse and the emergence of resistance in major bacterial
pathogens. Therefore, surveillance of antimicrobial resistance, and educational and campaign
activities for appropriate use of antibiotics and vaccination to prevent invasive pneumococcal
diseases are important steps for prevention and control of antimicrobial resistance.
9th Asian RTI Forum
7–8 March 2015
Sheraton Saigon Hotel & Towers, Ho Chi
Minh City, Vietnam
8 9
Antibiotic Stewardship Against Antimicrobial Resistance:
Are We Winning or Losing?
Christopher Lee
Sungai Buloh Hospital, Selangor, Malaysia
Professor Christopher Lee is head of the Infectious Diseases Unit at Sungai Buloh Hospital, Selangor
and is a visiting consultant for the Infectious Diseases unit at the National Heart Institute, Kuala
Lumpur.
As hospitalised patients become more complex to treat, the increasing prevalence of
antimicrobial resistance in all healthcare sectors represents a serious threat. Over the past two
decades, the world has seen a sharp increase in antimicrobial resistance in almost all pathogen
classes. With the increasing complexity of infections and a paucity of new antimicrobials in the
drug development pipeline, the future of successful antimicrobial therapy is not encouraging.
Antimicrobial stewardship can provide all clinicians with tools to prevent the overuse of this
precious and common resource, and will help to control the increase in antimicrobial resistance.
The increase in resistance has also finally caught the attention of influential international
healthcare organizations, including the WHO, which made antimicrobial resistance the theme of
its 2011 World Health Day.
In 2010, the Centers for Disease Control and Prevention launched ‘Get Smart for Healthcare’,
a campaign focused on improving antibiotic use in inpatient healthcare facilities in order to
prevent misuse of antimicrobials and to promote antimicrobial stewardship. These campaigns
help to draw attention to the clinical challenges that practitioners face on a day-to-day basis. The
various strategies in antimicrobial stewardship span a broad spectrum of interventions including:
healthcare financing, pharmacy procurement, quality drug manufacturing, and even the use of
antimicrobials in agriculture. Nevertheless, the day-to-day decision-making process in all clinical
settings faces the biggest challenge when antimicrobial therapy is being considered or started.
Guidelines have been issued from a wide range of international agencies for the development and
implementation of active antibiotic stewardship programmes in hospitals. A multidisciplinary
team, including at least an infectious disease physician and a clinical pharmacist, is frequently
required. Multiple strategies are available, including prospective audit with feedback to the
provider, education and antimicrobial restriction.
Interventions have had a positive effect on optimisation of antimicrobial use, reduced costs and
bacterial resistance; however, studies showing improvement in patient outcomes are sparse.
This may be confounded by several factors, including trial design and the lack of control for co-
interventions. Some of the common strategies in antimicrobial stewardship that are frequently
implemented will be discussed, including the role of the individual practitioner.
Product Safety and Quality: an Act of Social and Ethical Responsibility (Discussion resulting from low prices, which tend to result in generic antibiotics being perceived to be cheap
about Generic Antibiotics) commodities rather than precious drugs that must be used with restrain and caution.
Paul Tulkens*
Université catholique de Louvain, Belgium Because antimicrobial resistance to available antibiotics is increasing dramatically, new
framework models for antibiotic discovery, development and commercialisation must be actively
Professor Paul Tulkens is Emeritus Professor and Invited Professor of Pharmacology, Drug sought to avoid moving towards an era of untreatable bacterial infections.
Development, and Rational Therapeutic Choices at the Faculties of Medicine and Pharmacy,
Université catholique de Louvain, Belgium. *With approval from the Belgian Common Ethical Platform – visa no. 15/V1/7383/066684

Generic drugs have become widely used following the expiration of patent protection for many
key molecules in our pharmacological armamentarium, and the possibility to produce and
distribute them at a price that is considerably lower than that of the original product as they do
not have to recoup the costs of discovery and clinical development.

Based on current American, European and most other national regulations, applicants for
registration of generic drugs are not required to provide the results of pre-clinical tests or clinical
trials if they can demonstrate that their medicinal product does the following:
1) has the same qualitative and quantitative composition in active substances and the same
pharmaceutical form as the original drug, and
2) for non-parenterally administered drugs, shows bioequivalence (by reference to the original
drug; assessed in Phase I-type studies in which the 90% confidence interval around the
geometric mean ratios of both AUC and Cmax for the generic and the reference drugs are
shown to fall within a predefined 0.80–1.25 acceptance limit for most drugs).
Recent work, however, suggests that this may not always ensure therapeutic equivalence.

Concentrating on antibiotics, we will review the evidence that some generics fail to achieve
similar efficacy when tested both in vitro (if using sufficiently sensitive techniques) as well as in
vivo (in pharmacokinetic/pharmacodynamic animal models). Case reports of failures or toxicities
with generics will also be reviewed. Problems related to slower and sometimes erratic dissolution
of intravenous forms, appearance of coloured compounds upon storage in the ward, the presence
of impurities, unacceptable deviations from nominal contents, and absence of contaminants
will also be discussed and illustrated. Finally, we will examine the risk of overconsumption

9th Asian RTI Forum

7–8 March 2015
Sheraton Saigon Hotel & Towers, Ho Chi
Minh City, Vietnam

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Abstract
Session II: Evidence-Based Best Practice in LTRI
Chair/Moderator: John Hurst
University College London Medical School,
London, United Kingdom

Antibiotics for CAP: From Clinical Trial to Practice
Tobias Welte
Hannover University School of Medicine, Hannover, Germany
Tobias Welte is Head of the Department of Respiratory and Infectious Disease Medicine at
Hannover University School of Medicine, Germany.
For many years the treatment of community-acquired pneumonia (CAP) seemed to be easy. The
main pathogens were known, the development of resistance of these pathogens was a negligible
issue, and recommendations for the treatment of these patients based on well-designed
randomised trials were available. In the USA there have been concerns about patients from
nursing homes, who have regular contact with the healthcare system, being at risk for multi-
resistant infections, and that they may need broader antibiotic coverage (so-called healthcare-
associated pneumonia, HCAP). However, these data could not be confirmed outside the USA, and
the whole concept of HCAP is more questionable than ever.
In recent years, however, there have been increasing problems in the treatment of CAP. Two major
problems are an increase in resistant pathogens and a slow increase in mortality, especially in
hospitalised patients. Macrolides are the main focus in terms of development of resistance. The
resistance to these antibiotics is increasing, not only against classical bacterial pathogens such
as Streptococcus pneumoniae and Haemophilus influenzae, but also against atypical pathogens,
and especially against Mycoplasma pneumoniae where resistance has risen dramatically. In
some Asian countries, the use of macrolides for CAP is more or less impossible because of
resistance problems. However, atypical pathogens play a major role in the aetiology of CAP;
some studies have demonstrated that the lack of efficacy against these pathogens was a major
reason for treatment failure.
Mortality from CAP is, on average, 6–8% and has not declined over decades; however, an increase
has been observed in most countries in recent years. The main reason for this seems to be
the changing demography resulting from an increase in life expectancy. Older people have a
higher risk of developing CAP and also a higher probability of dying from this disease. Clinically
significant co-morbidities such as severe heart failure significantly increase the mortality rate.
For these patients at risk of a more complicated disease course and a higher probability of
mortality, an early and reliably effective therapy is essential. Bactericidal properties and good
tissue penetration resulting in high concentrations in the infected tissue, in addition to good
compatibility with a low rate of serious side-effects, are prerequisites for effective therapy in
elderly patients. Considering the increasing rate of resistance and an older, sicker population of
CAP patients, respiratory fluoroquinolones are the group of antibiotics that come closest to the
described requirements. They are characterised by a broad spectrum of activity against atypical
and other resistant pathogens, are highly bactericidal, and have excellent tissue penetration. In
addition, a low rate of side-effects has been demonstrated in many studies that enrolled elderly
patients. Respiratory fluoroquinolones undoubtedly represent a reliable alternative therapy for
CAP patients.

9th Asian RTI Forum

7–8 March 2015
Sheraton Saigon Hotel & Towers, Ho Chi
Minh City, Vietnam

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Antibiotics for AECOPD: Making the Right Choice outcomes have repeatedly demonstrated certain clinical characteristics to be associated with
Sanjay Sethi treatment failure or early relapse. Antibiotic recommendations for exacerbations have therefore
State University of New York, Buffalo, New York, USA incorporated the need to quantify the risk for poor outcomes of an exacerbation and early
aggressive antibiotic treatment for high risk patients.
Sanjay Sethi is Professor and Division Head in the Department of Medicine at the University at
Buffalo, SUNY, and a staff physician at the Division of Pulmonary, Critical Care and Sleep Medicine In conclusion, a re-appreciation of the role of bacterial infection in COPD has led to new efforts to
at the Western New York Veterans Administration HealthCare System in Buffalo, New York, USA. better treat these infections with currently available antibiotics. Applying a risk stratification takes
into account concerns of disease heterogeneity, antibiotic resistance and judicious antibiotic use.
Maintenance of a sterile lung environment is dependent on a very efficient innate lung defence
system, which is multi-faceted as well as redundant. In chronic obstructive pulmonary disease
(COPD) patients, this innate lung defence is disrupted, and recurrent acute and chronic infections
become prevalent. Acute infections present clinically as exacerbations of COPD (AECOPD).
Exacerbations are now regarded as a major contributor to the morbidity, mortality and healthcare
costs associated with COPD.

Exacerbations are inflammatory events caused mostly by bacterial and viral infection. The
causative role of bacteria in exacerbation is supported by bronchoscopic isolation of bacteria
from distal airways, molecular epidemiology of bacterial isolates, and studies of host immune
and inflammatory response in exacerbations. The traditional model of exacerbation pathogenesis
being related to ‘bacterial load’ has been replaced with a ‘new strain acquisition’ model.

There is a prevailing belief that all AECOPD are self-limited, and therefore even if they are bacterial,
they do not need to be treated with antibiotics. Past and recent studies dispute this notion,
with clinical failure and/or relapse rates at 1 month of 20–50%. Placebo-controlled antibiotic
trials and large observational studies in exacerbations of COPD demonstrate significant clinical
benefits of antibiotic treatment in moderate and severe episodes. Observational studies support
the benefit of antibiotic use in AECOPD in both outpatient and inpatient settings.

Whether antibiotic choice makes a difference in AECOPD outcomes has also been clarified
recently. In a bacterial infection, the primary aim of treatment should be to eradicate the
offending pathogen. Recent data from the MAESTRAL trial show a clear correlation between
bacterial eradication and a successful clinical outcome. Other studies, such as the MOSAIC and
GLOBE studies, have shown that time to next exacerbation differs among antibiotics. Therefore,
matching the antibiotic to the AECOPD patient is desirable. Observational studies of exacerbation

9th Asian RTI Forum

7–8 March 2015
Sheraton Saigon Hotel & Towers, Ho Chi
Minh City, Vietnam

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Biomarkers in Practice: Making an Impact on Patient Management
John Hurst
University College London Medical School, London, United Kingdom
John Hurst is currently a Reader in Respiratory Medicine at UCL, Medical School and Honorary
Consultant at Royal Free London NHS Foundation Trust from October 2007.
Chronic obstructive pulmonary disease (COPD) is a long-term condition of immense and increasing
global importance. Much of the morbidity and mortality relates to deterioration in respiratory
health, termed ‘acute exacerbation’ (AECOPD). The risk of exacerbation varies between individuals
with COPD, and it is now recognised that there is an exacerbation-susceptibility phenotype. In
addition to the heterogeneity inherent in COPD, exacerbations are also diverse events resulting in
a second tier of complexity. Exacerbations are often caused by respiratory viruses and/or changes
in colonising bacteria. Key clinical questions in relation to AECOPD include what is the best way
to identify who is at risk of exacerbation, and how can the clinician predict the causes, course and
consequences of an exacerbation?
It has been suggested that measurement of ‘biomarkers’ might provide practical answers
to these questions. A biomarker has been defined as “a characteristic that is objectively
measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or
pharmacological responses to a therapeutic intervention”. There are existing and novel data on
the role of biomarkers in AECOPD, and these will be discussed at the session. In particular, we
will review studies that have examined biomarkers in relation to the following everyday clinical
questions:
1) How do we differentiate AECOPD both from other causes of symptom deterioration (such as
pneumonia), and from stable disease?
2) How do we determine exacerbation aetiology, and therefore response to specific therapies
such as antibiotics?
3) How do we predict exacerbation susceptibility, and the risk of recurrent exacerbation?
9th Asian RTI Forum
7–8 March 2015
Sheraton Saigon Hotel & Towers, Ho Chi
Minh City, Vietnam
16
Lung Microbiome and its Potential Role in COPD
Sanjay Sethi
State University of New York, Buffalo, New York, USA
Sanjay Sethi is Professor and Division Head in the Department of Medicine at the University at
Buffalo, SUNY, and a staff physician at the Division of Pulmonary, Critical Care and Sleep Medicine
at the Western New York Veterans Administration HealthCare System in Buffalo, New York, USA.
It was widely believed that airway infection in chronic obstructive pulmonary disease (COPD)
was a static process, with patients colonised by the same bacteria pathogen for long periods
of time. This was thought of as an epiphenomenon with little relevance to COPD pathogenesis
and the occurrence of exacerbations. Recent findings have changed this paradigm dramatically,
demonstrating that infection in COPD is dynamic, and acquisition of new strains of bacteria is
the predominant mechanism of exacerbations. Though conventional microbiology is important
in understanding microbial causation of exacerbations, it is old technology with clear limitations.
Only 10–30% of bacteria associated with the human body are recovered with standard culture
techniques. In contrast, the yield of potentially pathogenic bacteria has been doubled by the use
of polymerase chain reaction (PCR) detection.
Microbiome studies of respiratory secretions could provide exciting new observations regarding
the bacterial causation of exacerbations of COPD. It could lead to discovery of new pathogens
that have been difficult to obtain using standard culture techniques. Furthermore, it appears that
bacterial species often associate with each other, and such association could have important
implications in exacerbation causation and treatment. Microbiome analysis of a respiratory
sample is most commonly done by PCR amplification of the 16S ribosomal RNA gene, a
highly conserved locus of the bacterial genome. Technological advancements have made the
acquisition of microbiome data straightforward, rapid and relatively inexpensive. However,
extensive computational analysis of the raw data is required. Though technologically superior to
conventional cultures, microbiome data interpretation in COPD has been a challenge.
Whereas studies with conventional microbiology found potential pathogenic bacteria to be
virtually absent in bronchoscopic samples in healthy controls, smoking and development of COPD
was associated with 35–50% incidence of isolation of pathogenic bacteria. In contrast, recent
studies that have applied microbiome techniques to determine whether smoking and COPD alter
the microbiota of the lower airways have found no or only minor differences from controls. These
contradictory findings could be explained by the extreme sensitivity of the microbiome technique
to upper airway contamination. Another possibility is that the trees are being lost when we look
at the forest, i.e. important differences in a few potential pathogens are difficult to discern when
the whole microbiome is explored.
17

There has been very limited exploration of the airway microbiome at the time of COPD
exacerbation. The vicious cycle hypothesis embodies the likely contribution of an altered
microbiome to COPD progression, with an unhealthy microbiome driving the inflammatory
process. Bacterial exacerbations likely represent abrupt major changes in the microbiome with
resultant large increases in airway and systemic inflammation.
Several challenges need to be tackled to fully utilise the benefits of microbiome research in
COPD. Paramount is the issue of upper airway and environmental contamination of lower airway
samples. It is unlikely that very low concentrations of bacterial pathogens are pathological.
However, significant concentration thresholds in microbiome data are currently undefined. Studies
have demonstrated that the microbiome differs in sputum, bronchoalveolar lavage and lung
parenchyma samples obtained from patients with COPD. The research question and feasibility
should dictate which compartment is sampled. In COPD exacerbation studies, repeated sampling
from patients with underlying severe COPD is often required, which would limit sampling to
non-invasive methods such as sputum collection. It is still unclear as to how the pathogenicity
of the various new microbes identified in microbiome studies would be determined, especially
for unculturable pathogens. Though various obstacles need to be overcome, lung microbiome
studies will ultimately provide new insights into how infection contributes to COPD.
9th Asian RTI Forum
7–8 March 2015
Sheraton Saigon Hotel & Towers, Ho Chi
Minh City, Vietnam
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Abstract
Session III: Facing Challenges in LRTIs
Chair/Moderator: Sanjay Sethi
State University of New York,
Buffalo, New York, USA
Managing CAP in an Area of Endemic TB
Tobias Welte
Hannover University School of Medicine, Hannover, Germany
Tobias Welte is Head of the Department of Respiratory and Infectious Disease Medicine at
Hannover University School of Medicine, Germany.
Many patients infected with tuberculosis present with lower respiratory tract symptoms and
a lung infiltrate. While the chest radiograph of patients is occasionally similar in community-
acquired pneumonia (CAP) and tuberculosis (TB), the classic presentations are quite different.
A prolonged clinical illness with a cavitary lung lesion is highly suggestive of TB, whereas an
abrupt clinical illness with airspace disease is most often CAP. The prevalence of TB in Asia
among patients presenting as CAP ranges from 2–5%, making this an uncommon pathogen.
As presented in a recently published study, there are five simple, though crucial, questions to ask
when active TB is suspected in patients admitted to the hospital with CAP. Unsurprisingly, weight
loss, night sweats, haemoptysis, exposure to Mycobacterium tuberculosis and younger age (<65
years) are among these questions.
As there is no perfect test for the diagnosis of TB infection, the question arises as to which test
should be used and who should be tested in order to obtain optimal results. Cumulative exposure
to a smear-positive index case for 8 hours or more is proposed as orientation. In comparison
to the tuberculin skin test, the emergence of interferon-gamma release assays (IGRAs) has
facilitated screening after unprotected TB exposure, as there is no booster phenomenon after
repeat testing, no need for a second appointment for test reading and no influence of bacillus
Calmette–Guérin vaccination on subsequent test results. IGRAs are not able to distinguish
remote from recent infection, and their ability to predict progression to active disease appears
to be limited to date. Although progression rates of up to 14% have been reported for close
contacts with a positive IGRA result, two recent systematic reviews and meta-analyses indicate
considerably lower progression risks.
When a patient with CAP is admitted to the hospital, M. tuberculosis could almost always be the
causative pathogen. However, administering an IGRA for all CAP patients would not be entirely
necessary or economical, as current IGRAs are not able to distinguish active TB from latent TB
infection.
19
Moreover, the sensitivity of IGRAs may be compromised by the immunological status of the
patient. Thus, a negative IGRA result does not rule out active TB. Furthermore, active TB might
be suspected in far too many contacts in populations with a high prevalence of (remote) latent
TB infection, and precious time may be lost while sputum results are awaited. Biomarkers such
as C-reactive protein or procalcitonin may help to distinguish between these entities. Most cases
of bacterial pneumonia are associated with an elevated procalcitonin whereas tuberculosis is
associated with a normal level. On average, patients with bacterial pneumonia become afebrile
within 3 days, whereas tuberculosis treated with appropriate multidrug therapy (not a single
agent) takes considerably longer. Most patients with TB, even when treated appropriately, have a
very slow radiographic response and often deteriorate initially. In contrast, bacterial pneumonia
usually has a rapid radiographic response especially in previously healthy young adults.
Fluoroquinolones are used widely for the treatment of respiratory tract infections. They are
frequently recommended as either first- or second-line therapy for CAP, and clinical trial results
and clinical experience suggest that they are extremely useful agents for this indication. It has
been suggested that fluoroquinolones should be limited in parts of the world where tuberculosis
is prevalent because the diagnosis of tuberculosis may be delayed if there is initial clinical
improvement with a quinolone, culture-negative tuberculosis may be more apparent, and
fluoroquinolone resistance may develop more quickly. Multiple studies to date have documented
a very low rate of fluoroquinolone-resistant tuberculosis throughout the world. Some observational
studies suggest fluoroquinolone resistance in TB may occur after prolonged or multiple exposures
to the drug. If a patient presents with a clinical illness suggestive of tuberculosis, fluoroquinolones
should not be used. However, if they are used in patients ultimately shown to have tuberculosis,
a short exposure to a potent fluoroquinolone is very unlikely to delay the diagnosis or lead to the
emergence of bacterial resistance.
9th Asian RTI Forum
7–8 March 2015
Sheraton Saigon Hotel & Towers, Ho Chi
Minh City, Vietnam
20
Gram-negative Pneumonia in the ICU
Kuang-Yao Yang
Taipei Veterans General Hospital, Taipei, Taiwan
Kuang-Yao Yang is the Director of the Respiratory Critical Care Unit and an Associate Professor in
the Department of Chest Medicine, Taipei Veterans General Hospital, Taiwan.
Gram-negative pneumonia is the most common hospital-acquired pneumonia (HAP) and a high
mortality disorder, which should be suspected if hospitalised patients develop the clinical signs
of infection with new infiltration on chest radiograph. Risk stratification should be based on
clinical presentation, time of onset following admission to the hospital and the potential for
multi-drug resistant (MDR) pathogens.
Management of Gram-negative pneumonia usually follows evidence-based guidelines. Published
guidelines include the American Thoracic Society/Infectious Diseases Society of America (2005),
the Association of Medical Microbiology and Infectious Disease Canada/Canadian Thoracic Society
(2008), and the Asian HAP Working Group (2008). Acinetobacter spp., Pseudomonas aeruginosa
and Klebsiella pneumoniae are the most frequent isolates from adults with HAP or ventilator-
associated pneumonia in Asian countries. These isolates are highly resistant to major antibiotics,
which could limit the therapeutic options in clinical practice. Furthermore, inappropriate initial
empirical antimicrobial therapy significantly increases the likelihood of pneumonia-related
mortality.
For those with suspected Gram-negative pneumonia, empirical antimicrobial therapy should
be initiated within 24 hours of diagnosis; antimicrobial treatment can be adjusted later when
microbiological and clinical response data become available. The choice of empirical antimicrobial
agents should be based on: 1) knowledge of the most likely pathogens in the local hospital
environment and their levels of antimicrobial resistance (patients with the most severe nosocomial
pneumonia are likely to have difficult-to-treat organisms, such as Acinetobacter spp. or resistant
P. aeruginosa), and 2) properties of the chosen antimicrobial, including the concentration at
the lung, pharmacodynamics, and the intrinsic in vitro activity of the antibiotic against the
likely pathogen(s). In patients unlikely to be infected with an MDR pathogen, intravenous/oral
monotherapy with an antimicrobial, such as ciprofloxacin, moxifloxacin or levofloxacin, ampicillin/
sulbactam or ertapenem is optimal. In patients likely to have MDR pathogens, the combination
of anti-Gram-negative antibiotics may be appropriate. In some patients with pneumonia who
are intubated and mechanically ventilated, inhaled antimicrobials may be an option. In addition
to treatment with the optimum antimicrobial agent, non-antimicrobial treatment (such as fluid
resuscitation, nutritional support and careful management of mechanical ventilatory support)
can contribute to improved outcomes in patients with Gram-negative pneumonia. Infection
control and risk reduction are also important elements of the management of Gram-negative
pneumonia.
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Non-Cystic Fibrosis Bronchiectasis: Breaking the Vicious Cycle
Kenneth Tsang
University of Hong Kong, Hong Kong
Kenneth Tsang is an Honorary Clinical Professor at the University of Hong Kong, and Clinical
Professor in the Bronchiectasis Research Team, State Key Lab, Guangzhou Medical College, China.
Bronchiectasis is a common disease in the developing world. While the aetiology of bronchiectasis
is diverse, many patients suffer from idiopathic disease, although the incidence of post-infective
bronchiectasis is likely to be higher in areas without sophisticated health care. The pathogenesis
of bronchiectasis is poorly understood. The hypothesis of the ‘vicious cycle’ in the pathogenesis
of bronchiectasis was originally proposed by Professor Peter Cole, and entails the consideration
of continued airway infection by colonising and infecting bacteria contributing to further
deterioration of airway inflammation, thereby aggravating the airway destructive process.
Bronchiectatic airways harbour bacteria such as non-typable Haemophilus influenzae in the
early stages, and Pseudomonas aeruginosa in the later stages of the disease. These bacteria are
not only capable of actively destroying the respiratory mucosa, by means of exotoxin production
and direct invasion, but they also slow the ciliary beat of respiratory epithelial cells causing
further impairment in airway clearance of bacteria and harmful secretions. Chronic infection
would, therefore, be allowed to persist in the tracheobronchial tree, which is usually sterile in the
healthy individual.
Airway inflammation in bronchiectasis, as reflected by neutrophil exit in the form of chronic sputum
production, could occur without acute infection. The exit of neutrophils from the bloodstream via
the airway capillary network causes chronic sputum production. Chronic inflammation permits
further breaching of the bronchiectatic airways and weakens airway defence. Therefore it is
important to consider treatment of patients with active bronchiectasis accordingly. Placebo-
controlled studies conducted by our group have shown the benefit of inhaled corticosteroid in
reducing airway inflammation and possibly also exacerbation frequency in bronchiectasis. The
use of long-term antibiotics seems desirable, but concerns over the development of antimicrobial
resistance and adverse reactions may restrict the use to inhalation formulations only. Recent
development of inhaled antibiotics could permit an attack on the vicious cycle, by concomitant
use of anti-inflammatory and anti-infective agents. The lack of enthusiasm in bronchiectasis
research has already resulted in under-development in the treatment of this frustrating disease,
and research in this area should be encouraged.
9th Asian RTI Forum
7–8 March 2015
Sheraton Saigon Hotel & Towers, Ho Chi
Minh City, Vietnam
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Looking to the Future: Building on the Bayer Heritage
Martin Springsklee
Bayer Pharma AG, Wuppertal, Germany
Dr Martin Springsklee is Vice-President and Head of Global Medical Affairs for the therapy areas
of Anti-Infectives and Men’s Healthcare of Bayer Pharma AG.
In an era of increasing resistance, the management of infectious diseases remains a challenge.
Bayer has always been at the forefront of antibiotic research, since the introduction of Prontosil
in 1935. Over the past 80 years, Bayer has successfully developed a number of new antibiotics
that have enabled clinicians to treat patients effectively.
The fluoroquinolones ciprofloxacin and moxifloxacin provide the best in class efficacy for a range
of infections. Avelox – a broad-spectrum third-generation fluoroquinolone – is licensed in many
countries for lower respiratory tract infections, as well as complicated skin and skin structure
infections, complicated intra-abdominal infections and pelvic inflammatory disease. The greater
efficacy of ciprofloxacin against Gram-negative infections means that it is still considered an
effective therapy for many nosocomial pneumonia patients, as well as for urinary tract and
surgical infections.
While over the past years there has been a steady decline of novel treatment options being
developed in the area of bacterial infections, the need for such novel options to better address the
treatment of resistant pathogens has increased considerably. This is why Bayer has specifically
looked into novel ways of improving the treatment of respiratory infections with existing agents,
by improved targeting of such agents to the site of infection. As a result, Bayer has developed
two novel antibacterial drug device combinations for aerosolized therapy, both of which have
demonstrated their potential to significantly improve drug delivery to the respiratory tract while
minimising systemic exposure. Amikacin Inhale* entered pivotal clinical trials during 2013 as
adjunctive therapy for Gram-negative pneumonia in intubated and mechanically ventilated
patients, and ciprofloxacin dry powder for inhalation* (DPI) has also entered Phase III clinical
trials for the prevention of exacerbations in non-CF bronchiectasis.
In addition, Bayer has strengthened its portfolio by establishing a development partnership with
Merck (Cubist Pharmaceuticals) to co-develop tedizolid*, a next-generation oxazolidinone with a
considerably improved profile vs linezolid. A joint clinical development programme is currently
underway, focusing on methicillin-resistant Staphylococcus aureus infections with the main
clinical indications ABSSSI and HAP/VAP.
*Amikacin Inhale, Ciprofloxacin Dry Powder for Inhalation (DPI), and Tedizolid are not yet approved
nor available in Vietnam.
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