Journal of Antimicrobial Chemotherapy Advance Access published June 10, 2015

J Antimicrob Chemother
doi:10.1093/jac/dkv157

Reviving old antibiotics

Ursula Theuretzbacher1*, Françoise Van Bambeke2, Rafael Cantón3, Christian G. Giske4,5, Johan W. Mouton6,7,
Roger L. Nation8, Mical Paul9, John D. Turnidge10 and Gunnar Kahlmeter11,12

1
Center for Anti-Infective Agents, Vienna, Austria; 2Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université
catholique de Louvain, Brussels, Belgium; 3Servicio de Microbiologı́a, Hospital Universitario Ramón y Cajal and Instituto Ramón y Cajal de
Investigación Biomédica (IRYCIS), Madrid, Spain; 4Clinical Microbiology, L2:02, Karolinska University Hospital, Solna, Stockholm, Sweden;
5
Department of Laboratory Medicine (LABMED), Division of Clinical Microbiology, Karolinska Institutet, Huddinge, Sweden; 6Department of
Medical Microbiology and Infectious Diseases Erasmus MC, Rotterdam, The Netherlands; 7Department of Medical Microbiology,
Radboudumc Radboud University, Nijmegen, The Netherlands; 8Drug Delivery, Disposition and Dynamics, Monash Institute of
Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia; 9Division of Infectious Diseases, Rambam Health Care Campus

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and Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel; 10School of Biological Sciences, University of Adelaide,
Adelaide, South Australia, Australia; 11Department of Clinical Microbiology, Central Hospital, Växjö, Sweden; 12Department of Medical
Sciences, Division of Clinical Bacteriology, Uppsala University, Uppsala, Sweden

*Corresponding author. Center for Anti-Infective Agents, Eckpergasse 13, 1180 Vienna, Austria. Tel: +43-14797024;
E-mail: utheuretzbacher@[Link]

In the face of increasing antimicrobial resistance and the paucity of new antimicrobial agents it has become clear
that new antimicrobial strategies are urgently needed. One of these is to revisit old antibiotics to ensure that they
are used correctly and to their full potential, as well as to determine whether one or several of them can help
alleviate the pressure on more recent agents. Strategies are urgently needed to ‘re-develop’ these drugs using
modern standards, integrating new knowledge into regulatory frameworks and communicating the knowledge
from the research bench to the bedside. Without a systematic approach to re-developing these old drugs and rigor-
ously testing them according to today’s standards, there is a significant risk of doing harm to patients and further
increasing multidrug resistance. This paper describes factors to be considered and outlines steps and actions
needed to re-develop old antibiotics so that they can be used effectively for the treatment of infections.

Introduction (i) Community-acquired infections caused by

ESBL-producing Enterobacteriaceae
As bacterial resistance to antibiotics increases, physicians more often
need to use old antibiotics that may still be active against some of Enterobacteriaceae that produce ESBLs are resistant to amino-
the existing MDR or XDR pathogens.1,2 These early, now resurgent, penicillins and cephalosporins, and are frequently co-resistant to
antibiotics were developed during the 1950s – 70s but some of fluoroquinolones, aminoglycosides and other antibiotics.4 The
them fell out of favour, mainly due to the availability of newer anti- two main enterobacterial species harbouring ESBLs with their
biotics with better tolerability, improved activity or more convenient associated co-resistances, namely Escherichia coli and Klebsiella
administration routes (Table 1). These old antibiotics were never pneumoniae, are recognized as important causes of community-
developed using a structured process for drug assessment and regu- acquired urinary tract infections (UTIs). Old antibiotics that are
latory approval. Current standards and the requirements for clinical increasingly used as revived oral treatment options for UTIs are
testing have evolved over time. As a consequence, revived old anti- fosfomycin trometamol,5 nitrofurantoin6 and mecillinam.7
biotics are being prescribed using the limited knowledge generated
50–70 years ago. This practice may carry significant risks for patient
outcomes, adverse events and the emergence of resistance. The lack (ii) Hospital-acquired infections caused by
of up-to-date evidence with these drugs underscores the import-
ESBL-producing Enterobacteriaceae
ance of ‘re-developing’ these drugs in academic and clinical settings
based on a concerted global strategy (Figure 1). The increasing prevalence of ESBL-producing Enterobacteriaceae
with co-resistance to other antibacterial drug classes has trig-
gered the empirical use of carbapenems and has led to increasing
Which old antibiotics need to be re-developed?
selection pressure and carbapenem resistance.8 Carbapenem-
Currently and into the near future, there are few or no treatment sparing agents are needed in hospitals; old drugs such as fosfomy-
alternatives for MDR or XDR bacterial strains causing the infections cin (intravenous) and temocillin to treat ESBL-producing bacteria
listed below.3 are increasingly used where available.9,10

# The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
For Permissions, please e-mail: [Link]@[Link]

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(iii) Severe hospital-acquired infections caused by affecting the safe and effective use of polymyxins, to identify
carbapenem-resistant Gram-negative bacilli gaps in knowledge and to set priorities for future research.12
Although the resistance problem is a global challenge, the
These bacteria are usually XDR and only susceptible to polymyxins
solutions may vary in different regions of the world. Reviving old
(colistin, polymyxin B) or sometimes tigecycline, fosfomycin and/
antibiotics as a quick solution to the thin antibiotic discovery
or some aminoglycosides.11 Polymyxins have had a substantial
and development pipeline requires agreement on the most prom-
resurgence as a last-line treatment over the last decade. A set
ising candidates for further action. Old antibiotics are useful to
of key objectives was developed in 2013 to explore the factors
avoid potential use of newer, costly antibiotics, which should be
reserved for the future. A process for prioritizing the most relevant
Table 1. First description of selected revived antibiotics and important candidates for re-development is required that
accounts for their availability internationally, the resistance land-
Antibiotic Year of first publication scape and the characteristics of the drug in a global and geo-
graphically diverse context.
Colistin29 1947
Chloramphenicol30 1947
Nitrofurantoin31 1954
Knowledge gaps

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Minocycline32 1966
Fosfomycin trometamol33 1969 Substantial progress has been made in key areas over the last
Mecillinam34 1975 20 years in the development of newer antibiotics. These include:
Temocillin35 1981 bioanalytical methods for accurate quantification of antibiotics
in biological fluids; better understanding of antimicrobial

∑ Prioritize old antibiotics that are still useful and need to be ‘re-developed’ and made more widely

available

∑ Identify the knowledge gaps and define the necessary high-quality studies

∑ Form collaborative groups with extensive complementary skills to ‘re-develop’ the prioritized

antibiotics

∑ Utilize existing initiatives and networks by coordinating the needed initiatives and merge them

into concerted global action

∑ Raise awareness and assure public funding for these programmes

∑ Create an open information and data hub for existing and new information about revived

antibiotics

∑ Organize dissemination and communication to all stakeholders

∑ Inform and engage regulatory agencies as well as governments, policy makers and payers to

ensure the availability of good quality drugs and information to guide their use

∑ Generate guidelines for the rational use of each old antibiotic and integrate them into clear

stewardship programmes

∑ Engage pharmaceutical producers to avoid the risk of shortage

∑ Monitor appropriate use of revived antibiotics by consumption and resistance surveillance

programmes

∑ Integrate the ‘re-development’ of old antibiotics into the global actions to fight antibacterial

resistance

Figure 1. Actions needed to revive useful antibiotics.

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pharmacokinetics/pharmacodynamics (PK/PD), including expos- demand for high-quality clinical trials and evidence. These early
ure–effect and exposure–emergence of resistance relationships; studies were often small, not randomized and had poor microbiol-
and dose-finding approaches and optimizing dosing regimens, ogy follow-up, and were therefore open to a range of biases and
including individualization, susceptibility breakpoint setting, data misinterpretation. Additionally, patient populations relevant
safety assessment and evidence-based therapy based on rando- to modern needs were usually not included and knowledge about
mized controlled clinical trials.13 These are also the most obvious appropriate dosing regimens was in its infancy. Contemporary
knowledge gaps for revived antibiotics. observational studies examining old antibiotics are plagued by
Although independent single studies may be published and unavoidable selection bias. Randomized controlled clinical studies
contribute to our new understanding of revived drugs, many in relevant patient populations using modern designs to improve
important gaps remain. As discussed in the following section, con- efficiency are needed to provide relevant information for improved
certed action can identify knowledge gaps concerning revived usage of revived antibiotics. Trials should target specific patho-
antibiotics using a collaborative re-development process. gens, especially resistant bacteria, or a group of indications rele-
vant to the antibiotic being assessed.
How to re-develop revived antibiotics? Although conducting high-quality clinical studies with limited
funding is challenging, there are advantages, such as the avail-
For recently approved antibiotics, the formal preclinical and clin- ability of clinical expertise with access to relevant patient popula-

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ical development processes are highly regulated and undertaken tions and the application of clinical endpoints that are not driven
predominately by a pharmaceutical company as an investment by marketing considerations or approval requirements. However,
for future returns. Re-development of old antibiotics is necessarily there are common problems of investigator-initiated randomized
different as these drugs are usually long out of patent protection. controlled trials in academic settings, such as single-centre stud-
Consequently, there is no financial incentive for the sometimes ies with a small number of patients, incomplete data collection,
numerous generic companies involved in their manufacture and prolonged study duration, slow recruitment over time and prema-
distribution to fund the necessary studies. Thus, public funding ture study termination. To face the problem of underpowered
through agencies such as the European Commission and the US studies, coordination of study protocols will allow comparability
National Institutes of Health is often the only option available.14,15 with respect to the interventions (dosing and schedule), outcome
The general structure of re-developing an antibiotic starts with a assessment, microbiological analysis, pooling of results and out-
systematic review to identify knowledge gaps and select the most comes. It is important to use available resources in the most effi-
important non-clinical and clinical studies. Ensuring sufficient cient way to avoid conducting many low-quality trials with limited
funding (preferably for a collaborative project that integrates a patient numbers instead of one or two multicentre high-quality
wealth of expertise) is the prerequisite for any further action. It randomized controlled trials.
is important to undertake early communication with regulatory
agencies, manufacturers and other involved players. Finally, issu-
ing treatment guidelines based on the findings of the new studies Regulatory and funding issues
and communicating these findings to the medical community
ensures the translation of knowledge to the bedside. Regulatory agencies must play an active role in the process of
The most advanced revived antibiotic is colistin, which is being reviving old antibiotics. In Europe the revived drugs have been
re-developed in academic clinical studies supported by public approved nationally, resulting in a high variability of approved
funding, albeit not based on a collaborative and structured pro- Summary of Product Characteristics (SmPC).18 Since 1995, the
cess. New methods and knowledge have superseded the original EMA has coordinated the evaluation of centrally authorized pro-
information, especially in the areas of PK/PD, analytical assays, ducts and national referrals to ensure consistency across the
dosing optimization (including in special patient populations), EU. Although regulatory pathways that allow the EMA to harmon-
toxicity and the emergence of resistance in relation to drug ize and update the SmPCs of old antibiotics across the EU are
exposure.16,17 The efficacy of colistin versus colistin/carbapenem available, the capacity of the EU regulatory network is limited
combination therapy is currently being tested in a well-designed and recommended updates to the SmPC are rare.19 In the USA,
randomized clinical trial in the EU-funded AIDA project (FP7 the FDA only permits updating of safety information. There is
HEALTH.2011.2.3.1-1—Preserving Old Antibiotics for the Future), clearly a need for harmonization of procedures with the main
supported by numerous non-clinical studies. A similar multi- regulatory agencies worldwide.20
centre, multi-country clinical trial, funded by the NIH (https://
[Link]/ct2/show/NCT00235690) is currently ongoing.
Both of these studies demonstrate the value of international col-
Responsible use of revived antibiotics
laboration and pooling results in challenging clinical settings. In Widespread antibiotic resistance follows the mismanagement of
the AIDA project other revived antibiotics, such as nitrofurantoin, antibiotics. If the use of revived antibiotics is indiscriminate or
fosfomycin trometamol, oral minocycline and rifampicin, are involves inappropriate dosing regimens, there will be growing resist-
being assessed, knowledge gaps identified and new information ance that will rapidly impede their efficacy. Colistin is a worrying
generated as a contribution to a public re-development process. example, having rapidly induced polymyxin resistance in centres
using it, leading to XDR and pan-resistant Gram-negative bac-
teria.21 – 23 Stewardship programmes supported by stringent infec-
Clinical study issues
tion control measures are imperative to prevent the loss of this
Most of the original clinical studies that supported the approval or resource. For last-resort antibiotics such as colistin, a simple strategy
early clinical use of old antibiotics do not satisfy our current that restricts prescribing to certain qualified prescribers could

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facilitate appropriate use. Infection control measures, such as iso- Conclusions

lating or cohorting patients who receive colistin, may limit the
spread of XDR bacteria. Revived old antibiotics have useful activity against otherwise MDR
bacteria. These antibiotics were not developed with the tools and
knowledge applied to modern agents. Vital gaps in the knowledge
Access, not excess needed to use these drugs appropriately require new solutions to
address the problems listed in this article. Strategies are urgently
Access to high-quality antibiotics is not a given in many parts of needed to re-develop these drugs using modern standards, inte-
the world. In low-resource countries, access to some of these grating new knowledge into regulatory frameworks and commu-
antibiotics or even future new agents is often not affordable. nicating the knowledge from the research bench to the bedside.
Access cannot be taken for granted in high-income countries Without a systematic strategy to re-develop these old drugs
either, as not all of the revived old drugs are universally approved and rigorously test them according to today’s standards, we risk
and available.24,25 Scandinavian physicians have successfully doing harm to patients or further increasing multidrug resistance.
used pivmecillinam for uncomplicated UTIs since the 1970s, but All stakeholders, from healthcare specialists, patients, payers and
in most countries pivmecillinam is not available. A similar situ- manufacturers to regulatory agencies and policy makers, need to
ation applies to fosfomycin iv, which is approved in Germany, be involved in creating a roadmap for taking old antibiotics for-

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Austria, France and Spain and a small number of Asian countries, ward and putting them to work again, safely and effectively.
and to temocillin, which is approved in only four European coun- The challenge now is to find much-needed resources—time,
tries (Belgium, Luxembourg, UK and France). finances and people—to fast-track the task of optimizing the
Ways of providing ready but controlled access based on local use of these potentially life-saving drugs and make them avail-
needs are required. National regulatory agencies and government able to everyone in need.
bodies are called upon to address this issue on a national basis.
Options include forming an international organization or using
an existing one to coordinate the distribution of old antibiotics cen-
trally. UNICEF could serve as an example of such an organization. Acknowledgements
Even if an old antibiotic is approved in a country, it does not Extensive discussions during the ESCMID Conference on Reviving old
guarantee access. Frequent drug shortages may lead to the use Antibiotics, October 2014 in Vienna, Austria, laid the foundation for this
of more expensive and broad-spectrum or less efficacious substi- article. A special thank you goes to the international faculty and experts
tute agents. These substitutes may further accelerate the emer- from science, healthcare, industry, global organizations and European
gence and selection of antibiotic resistance. The problem has Agencies as well as participants from 45 countries who discussed and
been recognized and the European Council has called upon the agreed on the issues requiring further action.
Member States and the European Commission to examine how
to keep effective antibiotics on the market.26

Funding
Sharing and communicating new knowledge This work was partly supported by the EU 7th Framework Program (AIDA
on old drugs grant Health-F3 – 2011-278348 to UT, JWM and MP). FVB is Maı̂tre de
Recherches of the Belgian Fonds de la Recherche Scientifique.
Not all clinical studies on revived antibiotics are published. Open
access to raw and unpublished data from old and new studies
could contribute to the evidence base around the re-development
process. A publicly funded, web-based, open-access repository of Transparency declarations
updated evidence on the use of antibiotics is needed to reduce the CGG has received speaker’s honorariums from Cubist, AstraZeneca, Pfizer,
time required for information gathering. Open access information and Cepheid. He has also received conference support from Cubist,
may speed up knowledge sharing. Local databases and processes, Cepheid and ABBiodisk. JWM has received research funding from
such as the Evidence summaries: unlicensed and off-label medi- Adenium, AstraZeneca, Basilea, Eumedica, Cubist, Pfizer, Polyphor, Roche
cines (ESUOMs) funded by the UK’s National Institute for Health and Shionogi. RC has received research founding from AstraZeneca, Cubist
and Care Excellence (NICE), could serve as model systems. and Ferrer. All other authors: none to declare.
Obvious challenges of an open data access portal are curating
the data, making them user-friendly and securing funding. Such
efforts require unprecedented collaborative (global) alliances at References
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