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The unrelenting rise of antimicrobial Greece [4]. KPC-Kp have been imported tigecycline is marred by high rates of
resistance (AMR) constitutes a serious from the United States to Israel, and from resistance among CRE [6] and a recent
threat to health worldwide. In the last Israel to Colombia, the United Kingdom, FDA safety warning [10]. The usefulness
decade, challenging multi-resistant bacteria and Greece. International spread of KPC- of colistin, the last drug with reliable in
have expanded while new antimicrobial Kp from Greece has occurred to at least vitro activity, is limited by toxicity, mod-
drug development has lagged [1] with little nine European countries since 2007 with erate efficacy, and emergence of resistance
coordinated containment action at the further transmission documented in four of [6]. Currently, not a single new agent to
global level. Of significant concern has them (Table 1 and Figure S1). CRE- treat CRE infections is on the horizon.
been the emergence of vancomycin-resis- producing metallo-b-lactamases of the These observations suggest that the inter-
tant Staphylococcus aureus, extensively drug- VIM family have become highly prevalent national spread of CRE constitutes a
resistant (XDR)-tuberculosis, and carbape- in Greece since their first detection in 2001 ‘‘cause for worldwide concern’’ [11].
nem-resistant Enterobacteriaceae (CRE). and spread to other countries in Europe
AMR in both humans and animals and America [5]. NDM-1-producing CRE The Shortcomings of Global
represents a complex global concern that likely originated in India or Pakistan and AMR Surveillance and Control
must be addressed ‘‘urgently and aggres- have spread to four continents [6,7].
sively’’ [2]. The International Health CRE have been associated with increased Surveillance of AMR-pathogens such as
Regulations (IHR), a legally binding agree- mortality and morbidity, and higher treat- CRE is patchy and limited by financial and
ment between 194 States Parties [3], ment costs, when compared to infections technical constraints in large parts of the
deserve critical examination with regard caused by susceptible strains [8,9], and have world. In some high-income countries,
to their applicability to AMR. Using the the potential to considerably increase the AMR data are compiled by publicly funded
example of CRE as point of departure, we risk associated with routine medical proce- surveillance networks such as EARS-Net, a
analyze and discuss the potential role of the dures. Although CRE have emerged in network of national surveillance systems in
IHR with respect to AMR. hospitals, they will eventually spread to the Europe, or by pharmaceutical company-
community, similar to ESBL-producing sponsored surveys. Informal networks, such
The Public Health Risk Posed by Enterobacteriaceae, resulting in untreatable as ProMED, also collect information,
CRE common infections in otherwise healthy although selectively and with a consider-
individuals. CRE, particularly NDM-1, are able time lag. This holds even truer for the
Enterobacteriaceae, a family that in- already prevalent in the community in India scientific literature.
cludes common pathogens responsible for and Pakistan [6]. Improving AMR surveillance is one of the
a large spectrum of disease, have been The alarming spread of CRE is juxta- key recommendations in a recent report [2].
sensitive to many antibiotics in the past. posed against our failure to develop new Without a global early warning system, the
Since the 1980s, the global spread of effective antimicrobials. The utility of spread of AMR often remains unnoticed
extended-spectrum b-lactamase (ESBL)-
producing Enterobacteriaceae has limited
therapeutic options, but until recently, Citation: Wernli D, Haustein T, Conly J, Carmeli Y, Kickbusch I, et al. (2011) A Call for Action: The Application of
the International Health Regulations to the Global Threat of Antimicrobial Resistance. PLoS Med 8(4): e1001022.
carbapenems were still a reliable treatment. doi:10.1371/journal.pmed.1001022
The recent emergence of CRE, resistant to
Published April 19, 2011
most classes of antibiotics, has necessitated
Copyright: ß 2011 Wernli et al. This is an open-access article distributed under the terms of the Creative
the use of third-line agents and combina- Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium,
tion therapy with doubtful therapeutic provided the original author and source are credited.
efficacy and increased toxicity [4]. Funding: The authors received no specific funding to write this paper. JC received financial support for a
Klebsiella pneumoniae harboring KPC sabbatical leave from the University of Calgary, Calgary, Canada.
(KPC-Kp) have become endemic in parts Competing Interests: JC has an unpaid relationship with the World Health Organization in the Department
of the United States, China, Israel, and of Global Alert and Response (Infection Prevention and Control Unit). All other authors have declared that no
competing interests exist.
Abbreviations: AMR, antimicrobial resistance; CRE, carbapenem-resistant Enterobacteriaceae; IHR, Interna-
The Policy Forum allows health policy makers tional Health Regulations; KPC-Kp, Klebsiella pneumoniae harboring KPC; PHEIC, public health emergency of
around the world to discuss challenges and international concern; WHO, World Health Organization; XDR, extensively drug-resistant
opportunities for improving health care in their
societies. * E-mail: stephan.harbarth@hcuge.ch
Provenance: Not commissioned; externally peer reviewed.
Table 1. Transmission of carbapenem-resistant Klebsiella pneumoniae from Greece to other European countries, 2007-2010.
Number of
Total Number Origin of Secondary Probability of Mechanisms of
Country Year of Patients Patients Cases the Greek Origin References Resistance
doi:10.1371/journal.pmed.1001022.t001
strains for which there are no suitable Plasmodium falciparum. ‘‘New or emerging just over half of respondents [13]. One of
treatments and which are of major public antibiotic resistance’’ is one of the exam- the main arguments against applying the
health importance, can be considered to ples listed in Annex 2 for application of the IHR to AMR events is that ‘‘the IHR are
fulfil at least two Annex 2 criteria, in first criterion. really intended for outbreaks of acute
particular ‘‘serious public health impact’’ Still, due to the nonspecific nature of disease’’ [14] rather than ‘‘acute-on-
and ‘‘international spread’’ (Table 2), and Annex 2 and limited WHO guidance, chronic’’ events like the relatively slow
should therefore be notified to WHO. some may counter that CRE (and other but relentless spread of AMR. However,
This argument has, in fact, been made for AMR) events are irrelevant to the IHR. we would counter that this reasoning is
XDR-tuberculosis and can be extrapolat- In a recent survey among National IHR inconsistent with the explicitly stated
ed to other types of significant new or Focal Points, a scenario describing a fatal purpose of the IHR ‘‘to prevent, protect
emerging extensively or pandrug-resistant hospital outbreak caused by pan-resistant against, control and provide a public
pathogens such as artemisinin-resistant K. pneumoniae was considered notifiable by health response to the international
Is the public health impact N The spread of CRE has a high potential for future impact on public N Not an immediate threat to public health; short-
of the event serious? health. ‘‘Public health impact weighs both the immediate and term impact difficult to quantify. The increased
potential future consequences of an event on the health of human attributable morbidity and mortality is mostly
populations’’ [15], although it is not clear whether ‘‘future’’ refers restricted to a minority group, i.e., hospitalized
to short-term or long-term consequences. patients. Low potential to cause visible community
N Treatment failure associated with AMR is one of the epidemics compared to infections such as influenza,
‘‘circumstances that contribute to high public health impact’’ cholera, or polio.
listed in Annex 2 [3].
Is the event unusual or N Novel resistance mechanisms, particularly pan-resistance, N Selection of resistant pathogens is an expected
unexpected? are by definition unusual and unexpected. consequence of the use of antimicrobials.
Is there any significant risk N Clear epidemiological links and cross-border movement N The international spread of CRE is slow compared to
of international spread? of individuals colonised or infected with CRE [7] (Table 1). the acute risk to public health caused by respiratory
viruses.
Is there any significant risk N In 2008/2009, Russia refused imports of pork and poultry products N In reality, no case of trade restrictions and no travel
of international travel or based on the presence of antibiotic residues [32]; a similar reaction restrictions due to CRE so far.
trade restrictions? to the presence of CRE in food items would not seem out of the
question in the context of increasing concern about AMR.
doi:10.1371/journal.pmed.1001022.t002
spread of diseases in ways that are awareness in multiple countries, allow interfere. Notification of an event to
commensurate with and restricted to early implementation of screening mea- WHO depends on it being detected
public health risks, and which avoid sures for persons at risk (e.g., international (requiring a functioning health system
unnecessary interference with internation- hospital transfers), and prevent the estab- and adequate laboratory capacities), and
al traffic and trade’’[3]. lishment of new resistant strains in unaf- reported to the National IHR Focal Point.
fected countries. Based on the experience There is concern that many States Parties
Why Should the IHR Be Applied to in Greece and Israel, Carmeli et al. are far from being compliant with the
the Global AMR Threat? recommend that countries ‘‘should be IHR’s minimum core capacity require-
The global threat posed by the spread of made aware of the problem and should ments for surveillance and response. Even
AMR cannot be addressed by individual have a preparedness plan ready for if relevant information filters through to
countries alone, but requires a coordinated implementation at a national level’’ [16]. the national level, notification decisions
international response. Recognizing the By authorizing WHO to make ‘‘standing may be under political control. The fierce
applicability of the IHR to AMR will serve recommendations’’ (Article 16), the IHR reaction of the Indian government to
as a ‘‘wake-up call’’ and strengthen global could facilitate the international dissemi- claims that NDM-1-producing CRE iso-
AMR surveillance and response, which nation of appropriate measures to counter lated in the UK originated in India casts
could in turn contribute to containing the the spread of AMR. doubt on the willingness of governments to
spread of AMR. While WHO has initiated Importantly, the IHR focuses on a report the existence of such events, in
several networks and provides guidance societal investment in core surveillance particular if economic interests (such as the
for reporting AMR, including WHONET, and response capacities at different levels income from medical tourism) are at stake.
none function as an early warning system. by setting minimum standards. WHO These obstacles are not specific to AMR-
Although very few AMR events would be pledges to collaborate with the States related events, and cannot serve as an
determined a PHEIC by the Director- Parties concerned ‘‘by providing technical argument against the application of the
General, notifications of events that fulfil guidance and assistance and by assessing IHR in this context.
the Annex 2 criteria could serve as alerts the effectiveness of the control measure in The final obstacles are a lack of expertise
and could be an important instrument in place, including the mobilization of inter- and capacities within WHO. Although
the chain of ‘‘the global early warning national teams of experts for on-site WHO vertical programs have successfully
function, the purpose of which is to assistance, when necessary’’. This is rele- focused on drug resistance in selected areas,
provide international support to affected vant for the spread of AMR given the including malaria and tuberculosis, WHO
countries and information to other coun- importance of appropriate infection con- arguably does not have the means to
tries if needed’’ [15]. The immediate trol measures. While details of these comply with its IHR mandate of offering
consequence of notification is to initiate measures need to be more closely defined, assistance to States Parties affected by the
an ‘‘exclusive dialogue between the noti- it is clear that the application of the IHR spread of multi-resistant bacteria. The
fying State Party and WHO concerning framework is invaluable for a coordinated dearth of leadership in this area was the
the event at issue’’ [15] and to make a joint global approach to AMR. object of a WHO resolution in 2005, but it
risk assessment. Once an event has been has been commented that ‘‘very little has
notified to WHO, and it is not determined What Are the Obstacles to Apply the taken place to implement the resolution
to be a PHEIC, WHO can communicate IHR to the Global Spread of AMR? WHA 58.27 since its passage’’ [17]. During
this information to other countries (Article Even if WHO and a majority of States the last World Health Assembly, the
11). The dissemination of information Parties considered that AMR should be Swedish Health Minister commented that
through the WHO Event Information addressed under the IHR, technical, ‘‘there is an increasing awareness about this
System (EIS) could expediently increase financial, and political obstacles might major health threat, but far from enough
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