Clinical Microbiology and Infection xxx (2017) 1e3

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Clinical Microbiology and Infection

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Commentary

Ensuring universal access to old antibiotics: a critical but neglected

priority
C. Pulcini 1, 2, 3, *, B. Beovic 3, 4, G. Be

raud 3, 5, 6, 7, 8, J. Carlet 8, O. Cars 9, P. Howard 3, 10,
G. Levy-Hara 11, 12, G. Li 13, D. Nathwani 14, F. Roblot 5, 15, M. Sharland 13
1)
Lorraine University, EA 4360 APEMAC, Nancy, France
2)
Nancy University Hospital, Infectious Diseases Department, Nancy, France
3)
ESCMID Study Group for Antimicrobial stewardshiP (ESGAP), Basel, Switzerland
4)
University Medical Centre Ljubljana and Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
5)
Centre Hospitalier Universitaire de Poitiers, Department of Infectious Diseases, Universit
e de Poitiers, Poitiers, France
6)
Universit
e Droit et Sant

e Lille 2, EA2694, Lille, France
7)
Hasselt University, Interuniversity Institute for Biostatistics and Statistical Bioinformatics, Hasselt, Belgium
8)
World Alliance Against Antibiotic Resistance (WAAAR), Paris, France
9)
ReAct e Action on Antibiotic Resistance, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
10)
Leeds Teaching Hospitals NHS Trust, Leeds, UK
11)
ISC (International Society of Chemotherapy) Antimicrobial Stewardship Working Group, UK
12)
Hospital Carlos G. Durand, Buenos Aires, Argentina
13)
Paediatric Infectious Diseases Research Group, St George's, University of London, London, UK
14)
British Society for Antimicrobial Chemotherapy (BSAC), Birmingham, UK
15)
Soci
et

e de Pathologie Infectieuse de Langue Française (SPILF, French Infectious Diseases Society), Paris, France

a r t i c l e i n f o

Article history:
Received 13 March 2017
Received in revised form
25 April 2017
Accepted 25 April 2017
Available online xxx
Editor: L. Leibovici
Despite most guidelines recommending old antibiotics that are
still effective, mostly available as generics, these antibiotics are not
universally marketed or available. This lack of availability may have
a serious impact on antibiotic prescribing. Physicians may be forced
to use less optimal, often broad-spectrum antibiotics instead. Such
alternatives may also be less effective, may have more adverse ef-
fects, and may drive the selection of resistance. For example, in the
treatment of sore throat, amoxicillin is used instead of penicillin.
Fluoroquinolones are used instead of nitrofurantoin, fosfomycin or
pivmecillinam for the treatment of cystitis, and co-amoxiclav or
cephalosporins for the treatment of skin and soft tissue infections
instead of appropriate oral formulations of antistaphylococcal
penicillins. Additionally, some old antibiotics such as temocillin or
* Corresponding author. Ce
line Pulcini, Centre Hospitalier Universitaire de Nancy,
Service de Maladies Infectieuses et Tropicales, Ho ^pitaux de Brabois, alle
e du Mor-
van, 54511 Vandoeuvre-Le s-Nancy, France.
E-mail address: celine.pulcini@univ-lorraine.fr (C. Pulcini).
i.v. fosfomycin are valuable alternatives for the treatment of some
resistant bacteria. The limited access to these old antibiotics is a
threat to antibiotic stewardship.
In 2011, the ESCMID Study Group for Antimicrobial stewardshiP
(ESGAP) showed that 22 out of 33 old but potentially useful anti-
biotics were marketed in fewer than 20 of the 38 included countries
in Europe, USA, Canada, and Australia; economic motives were the
major reason for not marketing these antibiotics [1]. ESGAP and the
international network ReAct (Action on Antibiotic Resistance)
updated this survey in 2015 [2]. The situation was worse than in
2011, with even fewer antibiotics available in the included coun-
tries. Again the economic situation was the main reason reported
for not marketing these antibiotics, including high registration
costs and small market size (limited volume sales and low prices),
leading to a perceived lack of return on investment for pharma-
ceutical companies. Other reasons were lack of demand (low use by
clinicians and absence of recommendation of these drugs in na-
tional/international guidelines), and lack of awareness or low pri-
oritization of the problem by health authorities. There are no
published data on this topic in low- and middle-income countries
(LMICs), but anecdotal reports suggest that the situation could even
be worse.
Besides this absence of marketing, there are also repeated and
prolonged shortages of supply for these antibiotics worldwide in
different settings. Quadri et al. showed that 148 antibiotics were in
short supply between 2001 and 2013 in the USA, with 22% of drugs
experiencing multiple shortage periods [3]. They also showed a
concerning rise in reported shortages since 2007, with an increase

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Please cite this article in press as: Pulcini C, et al., Ensuring universal access to old antibiotics: a critical but neglected priority, Clinical
Microbiology and Infection (2017), http://dx.doi.org/10.1016/j.cmi.2017.04.026
2 C. Pulcini et al. / Clinical Microbiology and Infection xxx (2017) 1e3
of 0.35 additional antibiotics experiencing shortage every month.
Antibiotics used against multidrug-resistant bacteria (such as car-
bapenems and colistin) were affected by these shortages and
extended periods of no supply. A 2011 US physician survey also
showed that more than half of the respondents reporting a
shortage declared that patient outcomes were negatively affected
as the alternative drugs were less effective, more toxic, or more
costly [4]. In many LMICs, lack of antibiotic supply in hospitals may
be due to budget constraints and/or bureaucracy, impeding pur-
chasing from the central or hospital administration, despite the
availability of drugs in the market. Less is known about antibiotic
shortages in Europe [5]. In the above-mentioned 2015 survey [2],
several participants spontaneously reported severe problems in
availability of some antibiotics due to shortages (for example, for i.v.
flucloxacillin, i.v. fosfomycin, ticarcillineclavulanic acid), even
though the documentation of shortages was not an objective of the
study. A European survey conducted among more than 600 hospital
pharmacists from 36 countries reported that antimicrobials were
the most affected therapeutics [6]. Causes for these shortages are
multiple and complex, including failures in manufacturing pro-
cesses, scarcity of raw materials, concentration of manufacturing in
emerging economies, pressure on profit margins, and sometimes
dependence on a single producer [7]. No studies have been con-
ducted to assess the exact consequences of antibiotic shortages on
patients' outcomes, but national agencies reported that some pa-
tients experienced negative outcomes because of a less effective or
more toxic alternative. Beyond the impact on patients, shortages
may undermine people's confidence in the public health system
and in national and supranational organizations' abilities to provide
adequate healthcare and supply systems. Despite this being a clear
global concern and a worldwide threat to national action plans to
combat antimicrobial resistance, no co-ordinated response has yet
been taken. A first step would be to set up standardized monitoring
systems to estimate the scale of the problem; this could be incor-
porated into the World Health Organization (WHO) planned sur-
veillance programmes of antimicrobial use, and also linked to
ongoing work at WHO on shortages [8]. A next step would be to
facilitate the dialogue between providers, national agencies and
international organizations to find sustainable ways to address
both availability and pricing. Existing procurement mechanisms
such as the EU Joint procurement agreement to facilitate medical
countermeasures and the Global Drug Facility could be used as a
template [9,10]. A European four-year project led by Co-operation
in Science and Technology (COST, http://www.cost.eu/COST_
Actions/ca/CA15105) will focus on promotion, manufacturing,
procurement disruption, clinical management of shortages, and the
impact on patient outcomes to propose a European solution.
Whereas the project covers all medicines, antimicrobials have been
identified as a key priority.
Finally, many paediatric formulations of old antibiotics have
very limited availability. Ensuring access to paediatric-friendly
formulations of antibiotics creates particular challenges. For anti-
biotics that have good oral bioavailability, suspensions are known
to offer superiority in terms of absorption compared with crushing
adult tablets or mixing the contents of capsules with food [11]. But
suspensions have many problems and increasingly dispersible
tablets are being used, although these are not always marketed
where tablets or capsules are readily available (cloxacillin,
oxacillin), requiring hospital pharmacies to produce their own on
site. Dispersible tablets offer advantages over liquid preparations
with regard to shelf life, transport and storage costs, especially in
LMICs where refrigeration may not be readily available and mini-
mization of cost is paramount to affordable access. The recent
development of mini-tablets (2e4 mm in diameter) which have
demonstrated good acceptance in trials of children aged from
Please cite this article in press as: Pulcini C, et al., Ensuring universal access to old antibiotics: a critical but neglected priority, Clinical
Microbiology and Infection (2017), http://dx.doi.org/10.1016/j.cmi.2017.04.026
6 months to 6 years shows promise [12]. For antibiotics adminis-
tered parenterally, vial sizes of powders for suspension may not be
appropriately sized for administration of neonatal doses, especially
extremely pre-term infants who require repeated and prolonged
courses of antibiotics. For example, fosfomycin powder for oral
suspension is produced in doses inappropriate for paediatric pa-
tients (3 g sachets, EU) and tobramycin for i.v. administration is
produced in 80 mg vials where the recommended neonatal dose is
4e5 mg/kg. Child-friendly formulations for some old antibiotics
have been withdrawn from the market (e.g. pristinamycin syrup in
France). Moreover, paediatric pharmacokinetic data for old antibi-
otics are generally limited, creating further challenges with
appropriate dosing in paediatric patients. Economic incentives tied
to pre-defined Target Product Profiles are needed together with
academic collaborations such as the European Paediatric Formu-
lation Initiative and non-profit product development partnerships
such as GARDP (Global Antibiotic Research & Development Part-
nership) to encourage production of paediatric antimicrobial
formulations.
In conclusion, one might question the value of the considerable
global investments currently underway in research and develop-
ment for new antibiotics without simultaneously making powerful
efforts to make better use of our existing ones. International
agencies and organizations such as WHO and the European Com-
mission could consider taking the lead in developing a strategy for
ensuring the sustainable production, registration, and availability
of old antibiotics that may help address growing problems of drug
resistance as well as addressing the serious shortage or complete
lack of other antibiotics (see recommended actions, Box 1). This
may require designing proposals that would facilitate their regis-
tration across countries, a greater presence of national govern-
ments in decisions and production, transferring technology to
other manufacturers, or providing appropriate and targeted eco-
nomic incentives to encourage their development and commercial
availability. Significantly improved global access to key older
Box 1
Suggested next steps for action
1 Define (through the WHO Essential Medicines List and/or
an ad-hoc WHO working group) the set of ‘key access’
antibiotics for which there should be universal access.
2 Access here could be defined as: ‘An adult or child are able
to receive when clinically required the appropriate anti-
biotic for their clinical infection syndrome at an appro-
priate dose, duration, formulation, quality and price.’
3 Monitor the current global availability of these key access
antibiotics. This includes both usedthrough the WHO
Surveillance on Antimicrobial Use programmedand
supply through a survey of global generic antibiotic pro-
ducers of these key access antibiotics, including the for-
mulations and cost. Monitor shortages through a common
centralized mechanism.
4 Conduct an antibiotic access gap analysis between clinical
need and appropriate medicine availability. This needs to
include an assessment of this variation by region and age.
5 Re-evaluate the pharmacokinetic/pharmacodynamic tar-
gets for these out-of-patent antibiotics in the context of
the global variation in rates of resistance.
6 Consider the potential roles and feasibility of a Global
Antibiotic Access and Conservation Fund, initially with the
objective of implementing the five actions mentioned
above.
 C. Pulcini et al. / Clinical Microbiology and Infection xxx (2017) 1e3 3

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concerns regarding antimicrobial agent shortages among infectious disease
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[5] Pauwels K, Huys I, Casteels M, Simoens S. Drug shortages in European coun-
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[6] www.eahp.eu/sites/default/files/shortages_report05online.pdf.
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Conflict of interest disclosure terminants, and solutions to drug shortages in Shaanxi Province, China: a
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[10] http://www.stoptb.org/gdf/whatis/.
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Please cite this article in press as: Pulcini C, et al., Ensuring universal access to old antibiotics: a critical but neglected priority, Clinical
Microbiology and Infection (2017), http://dx.doi.org/10.1016/j.cmi.2017.04.026