Journal of Antimicrobial Chemotherapy (2007) 59, 347 358

doi:10.1093/jac/dkl537
Advance Access publication 8 February 2007

The use of erythromycin as a gastrointestinal prokinetic agent in adult

critical care: benefits versus risks
Catherine V. Hawkyard and Roland J. Koerner*
Department of Medical Microbiology, Sunderland Royal Hospital, Sunderland SR4 7TP, UK

Keywords: modular evolution, non-antimicrobial activities

Introduction
The macrolides are a group of closely related antibiotics, mostly
produced from Streptomyces.1 The most important therapeutic
macrolides are characterized by a 14-, 15- or 16-membered lactone
ring. Erythromycin consists of a mixture of compounds in which
erythromycin A, which has a 14-member lactone ring, is the active
macrolide component.2 Erythromycin, discovered in 1952,3 was
the first macrolide to be introduced into clinical practice. The 14(including erythromycin, clarithromycin and roxithromycin), 15(including azithromycin) and 16-membered ring macrolides share
a broad spectrum of antimicrobial activity, exhibiting action
against Gram-positive and Gram-negative bacteria. Consequently,
erythromycin A (and newer macrolides such as clarithromycin,
roxithromycin and azithromycin) are used extensively as a major

alternative to the use of penicillins and cephalosporins in many

countries for the treatment of infections, especially those caused
by b-haemolytic streptococci and pneumococci.4
However, there has been rapid spread of bacterial resistance
within common pathogens; resistance to erythromycin A within
Streptococcus pneumoniae and a drop in efficacy of macrolides
upon b-haemolytic streptococci such as Streptococcus pyogenes
has been recorded worldwide.5 This has prompted the development of the ketolide group of antibiotics (a semi-synthetic
derivative of erythromycin A).5 The ketolide telithromycin
retains activity against isolates resistant to erythromycin A in S.
pneumoniae and S. pyogenes.1
Macrolides have been found to have pharmacodynamic
properties beyond their antimicrobial mode of action.6 10 Some
of these include anti-inflammatory and immunomodulatory

.....................................................................................................................................................................................................................................................................................................................................................................................................................................

*Corresponding author. Tel: 44-191-5656256; Fax: 44-191-5410531; E-mail: Roland.Koerner@chs.northy.nhs.uk

.....................................................................................................................................................................................................................................................................................................................................................................................................................................

347
# The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Downloaded from http://jac.oxfordjournals.org/ by guest on December 17, 2016

Erythromycin A, the first macrolide, was introduced in the 1950s and after years of clinical experience
it still remains a commonly relied upon antibiotic. In the past, pharmacodynamic characteristics of
macrolides beyond antimicrobial action such as anti-inflammatory and immune-modulating properties
have been of scientific and clinical interest. The function of erythromycin as a prokinetic agent has
also been investigated for a range of gastrointestinal motility disorders and more recently within the
context of critically ill patients. Prokinetic agents are drugs that increase contractile force and accelerate intraluminal transit. Whilst the anti-inflammatory action may be a desirable side effect to its antibiotic action, using erythromycin A merely for its prokinetic effect alone raises the concern about
promoting emergence of macrolide resistance. The objectives of this review article are: (i) to briefly
summarize the modes and epidemiology of macrolide resistance, particularly in respect to that found
in the Streptococcus species (a potential reservoir for the dissemination of macrolide resistance on
the critical care unit); (ii) to discuss in this context the evidence for conditions promoting bacterial
resistance against macrolides; and (iii) to assess the potential clinical benefit of using erythromycin A
as a prokinetic versus the risks of promoting emergence of macrolide resistance in the clinical setting.
We conclude, that in view of the growing weight of evidence demonstrating the potential epidemiological impact of the increased use of macrolides upon the spread of resistance, versus a lack of sufficient
and convincing evidence that erythromycin A is a superior prokinetic agent to potential alternatives
in the critically ill patient population, at this stage we do not advocate the use of erythromycin A as a
prokinetic agent in critically ill patients unless they have failed all other treatment for impaired gastrointestinal dysmotility and are intolerant of metoclopramide. Further large and methodologically robust
studies are needed to ascertain the effectiveness of erythromycin A and other alternative agents in the
critically ill.

Review

Objectives of this review

The objectives of this review are the analysis of the data
supporting the potential therapeutic benefit of erythromycin A
compared with other alternatives such as metoclopramide as a
prokinetic agent and the assessment of the risk of potential concomitant contribution to the emergence of macrolide resistance.
As the starting point of our reasoning we will briefly:
(i) outline the antimicrobial mode of action of and modes of
antimicrobial resistance to erythromycin A and the other macrolides and ketolides, with particular emphasis on the streptococcal
species and the Enterobacteriaceae as a reservoir of genetic
elements encoding resistance; (ii) analyse the data demonstrating
that increased use of macrolides contributes to the emergence of
antibiotic resistance; and (iii) review the data supporting the
potential therapeutic benefit of using erythromycin A against
other alternatives such as metoclopramide as a prokinetic agent.
We will then comment upon what recommendations should be
made upon its use as a first-line prokinetic versus other potentially available alternative agents in the critical care setting.

Summary of the antimicrobial action of

erythromycin
Erythromycin A inhibits both formation of the 50S subunit27 and
RNA-dependent protein synthesis in bacteria at the step of chain
elongation by reversibly binding to the 50S ribosome subunit and
blocking transpeptidation/translocation reactions.28 It can also
inhibit messenger RNA (mRNA) translation at the level of the
23S rRNA (mostly interacting with domain V out of six domains
IVI) and ribosomal proteins L4 and L22, which are part of the
50S subunit.5 Erythromycin A can share common binding sites
with other macrolides and other antibiotics, interfering with their
binding to the ribosome. The macrolides mainly achieve inhibition of protein synthesis by binding in the exit tunnel of the
ribosome where the evolving peptide is primarily formed by 23S
rRNA. This tunnel is a dynamic structural component where
interactions between the evolving peptide and the ribosome are
taking place. These interactions influence the progression of synthesis as well as the activity of the ribosomal peptidyl transferase.29 The ribosomal proteins L4 and L22 form a constriction of
the exit tunnel. Macrolides bind in close proximity to this constriction thus blocking the exit tunnel. It appears that the exact
location of the protein synthesis inhibition seems to be dependent
on the amino acid sequence of the evolving peptide. The ketolides
such as telithromycin represent the most recent subgroup of
the macrolide antibiotics. They demonstrate increased binding to
the ribosome when compared with the older macrolides.30,31 The
current understanding of the structureactivity relation of the
various macrolides has been reviewed in detail.32
Macrolides are indicated for use as drug of choice for when
atypical pneumonia, such as that caused by Legionella pneumophila, is suspected. They are also an important alternative to
penicillin in respiratory tract infections,33 infections caused by
groups C and G streptococci, S. pneumoniae and S. pyogenes
and for rheumatic fever prophylaxis.4,34 Consequently, they are
extensively used drugs, especially in the treatment of streptococcal and respiratory tract infections. Ketolides retain activity
against Gram-positive isolates resistant to erythromycin A and
are also used in the treatment of respiratory tract infection.5
Owing to their different molecular structure, the target site of
ribosomal interaction in ketolides differs from the other macrolides, hence they appear unaffected by some currently known
mechanisms of resistance.35

Mechanisms of macrolide resistance

Bacteria possess a huge and continuously evolving variety of
resistance mechanisms to antibiotics. This review is concerned
with the use of macrolides and their consequent impact on emergent resistances, particularly among streptococcal species, as
they are pathogens that commonly cause infections for which
macrolides are indicated. It has been reported that increased antibiotic pressure caused by macrolides may be linked with increased
macrolide resistance in bacteria such as streptococci,21,22,36,37
but it is also important to understand the principle that emergence of new resistances in relation to the use of a certain antibiotic may not be limited purely to the group of antibiotics to
which it belongs. Cross-selection can play a crucial role in the
spread of resistant clones; for example, Karl Kristinsson has
demonstrated that the abundant usage of co-trimoxazole in

348

Downloaded from http://jac.oxfordjournals.org/ by guest on December 17, 2016

effects. These are beyond the scope of this paper to discuss in

further detail having already been extensively reviewed.6 10 In
these clinical situations, it is noteworthy that the macrolides are
being used, often primarily, for their antibiotic effect on the diseases and the aforementioned extra-antibiotic effects are an
addition to this.
More recently, another extra-antibiotic effect of macrolides has
been exploited; their function as a gastrointestinal prokinetic.11
Prokinetic agents are drugs that increase contractile force and
accelerate intraluminal transit.12 Many studies have been carried
out in a wide variety of patient populations and disorders, including gastroesophageal reflux in children,13 diabetic gastroparesis14
and functional dyspepsia.15 This has been investigated in erythromycin A and, to a lesser extent, clarithromycin.16 Only the prokinetic action of erythromycin A has been studied in the critically
ill population to date and therefore we concentrate upon this
macrolide as a prokinetic in this review, although in terms of
macrolide and ketolide consumption (for whatever purpose), we
feel that impact on emergence of resistance is likely to be similar
whichever group member is used. In contrast to the antiinflammatory action, which has a desirable association with the
indication for an antibiotic, the prokinetic effect has nothing to do
with the primary indication of antibiotics. Although the number
of studies investigating the use of erythromycin A as a prokinetic
in the critical care setting is small, and few of these comprise
large sample sizes, there are already authors who advocate the use
of macrolides such as erythromycin A purely for its prokinetic
properties.17,18 This approach has been supported by guidelines
recommending or discussing the use of erythromycin A as a
means for the prevention of aspiration of gastric content, a feared
complication in the intensive care setting.19,20 In contrast to this,
and in light of increasing reports indicating spread of macrolide
resistance, especially within the streptococcal species,21 26 we
have concerns about the use of antibiotics for this non-antibiotic
property. Therefore, we feel that use of erythromycin A as a prokinetic in the critically ill may not be justified and that the evidence for its beneficial effect needs to be weighed up against the
risk of further emergence of antibiotic resistance associated with
the increasing usage of macrolides.

Review

Efflux systems
This resistance mechanism was first reported in 1996.40 Those possessed by streptococci tend to be coded for by mef (for macrolide
efflux) genes, which are located on chromosomes, or on mobile
genetic elements within the chromosome and mostly belong to the
major facilitator (MF) superfamily, which is specific for 14- or
15-membered ring macrolides.43 The first described mef gene was
found in S. pyogenes in 1996 and named mef(A).44 The mef gene
found in S. pneumoniae was initially called mef(E).45 These two
genes share 90% identity at the DNA level and at the time were
detected using a PCR method that did not distinguish between the
two variants. In 1999, Roberts et al. suggested that both genes
should be referred to as mef(A).42,45,46 However, it has subsequently been shown that the two genes are carried by two different non-conjugative elements in S. pneumoniae 47,48 and have
disseminated differently among microbial species,49 prompting
Klaassen and Mouton, in their recent minireview,49 to suggest that
insight into the properties of the mef genes now acts in favour of
maintaining the difference between mef(A) and mef(E) where
efforts have been made to discriminate between them, for instance
for S. pneumoniae, and to use the description mef when no efforts
were made to distinguish between variants. Therefore, for future
description in this review, we will refer to these genes and their
variants as mef. The resulting resistance pattern against the 14- and
15-membered ring macrolides (including erythromycin, clarithromycin, roxithromycin and azithromycin) but not 16-membered
ring macrolides, streptogramins or lincosamides, even after induction by erythromycin, is known as the M phenotype.40 The M
phenotype is associated with expression of low-level resistance to
macrolides in S. pneumoniae (MIC90 4 mg/L),48 viridans group
streptococci50,51 and S. pyogenes. 26,40 It can be induced by 14- and
15-membered ring macrolides, but not by other macrolides.4 mef
genes have been shown to be carried on transposons.48,52 They
have also been found in combination with another macrolide
resistance conferring gene, erm (see below), in S. pneumoniae,
S. pyogenes or Streptococcus agalactiae strains.39,53,54 Others have
postulated that resistance determinants, such as mef for erythromycin, are genetically linked with resistance determinants for
tetracycline and chloramphenicol.55 Recently, it has been shown

that the activity of the new ketolide, telithromycin, is reduced by

efflux in S. pyogenes.56

Target site modifications

This is the most widespread mechanism of resistance to macrolide antibiotics found in bacteria and involves the modification
of the 23S rRNA target of the antibiotics by an adenine-specific
N-methyltransferase (methylase),57 which then renders the antibiotics unable to bind. Overlapping binding sites on the 23S
rRNA leads to cross-resistance to macrolides (14-, 15- and
16-membered ring), lincosamides and streptogramins B: the
MLSB phenotype.57 Over 40 erm (erythromycin A ribosome
methylase) genes coding for these methylases, mostly associated
with transposons on chromosomes or plasmids, have been
characterized in the last two decades and have been found in
different species, genera and isolates.42 Four major classes are
found in pathogens; erm(A), (B), (C) and (F). The genes associated with the MLSB phenotype in streptococci include erm(A),
erm(B), erm(C), erm(F) and erm(Q).42 The erm genes are an
integral part of the genome of macrolide-producing bacteria.
There is evidence suggesting that these genes were disseminated
to clinical pathogens by horizontal gene transfer.58 erm genes
are now often associated with other antibiotic resistance genes,
e.g. erm(B) and tet(M),42 which again illustrates the potential
opportunity for bacteria to acquire multiple resistance as
bacterial populations are exposed to macrolides.
Expression of the MLSB phenotype can be constitutive or
inducible. In inducible expression bacteria produce inactive
mRNA that is unable to produce methylase. It only becomes
active in the presence of a macrolide inducer, which leads to
rearrangements in the rRNA allowing the methylase sequence
to be translated.4 Resistance can be induced by 14- and
15-membered ring macrolides but not by 16-membered ring
macrolides.5 Ketolides are also unable to induce MLSB resistance and are active against inducible erm-containing streptococci.5 Diversity of gene expression occurs between bacterial
hosts possibly in relation to differences in ribosomal structure or
methylase expression and leads to the range of phenotypes seen
in MLSB resistance.4,42 The constitutive phenotype involves production of active methylase without pre-exposure to antibiotics
and is less variable, generally resulting in high-level cross-resistance to macrolides, lincosamides and ketolides.59 Isolates with
constitutive erm gene expression can be distinguished from inducible isolates by their MICs being unaffected whether or not
they are in the presence of an inducer.42
As mentioned above, these are not the only mechanisms of
macrolide resistance and as bacterial sophistication continues to
develop, other mechanisms such as the target mutations of
domain V in the 23S rRNA and ribosomal proteins in pneumococci or esterases in Enterobacteriaceae may soon play a more
significant part in the emergence of resistance.60

Summary of the prokinetic action of erythromycin A

Mode of action of erythromycin A on the gastrointestinal
system
Erythromycin A and other 14-membered ring macrolide antibiotics have a gastrointestinal motility stimulating effect; it has

349

Downloaded from http://jac.oxfordjournals.org/ by guest on December 17, 2016

Iceland has contributed to the spread of a penicillin-resistant

clone of serotype 6 S. pneumoniae.38 It is also known that
during the transfer of genetic material between isolates (including S. pyogenes),39 that genes conferring resistance to macrolides can be passed on in combination with other resistance
genes [for example tet(O) conferring resistance to tetracyclines],39 resulting in multidrug-resistant isolates.
Several mechanisms of resistance to macrolides have been
described, including efflux, methylation (23SrRNA), 23SrRNA/
ribosomal protein mutations, esterase hydrolysis and inactivation
by 20 -OH-phosphorylase/20 -OH-glycosidase.4,5,40 Streptococci
possess many mechanisms by which they become less susceptible to the effects of macrolide (and other) antibiotics which
include genes coding for methylases [erm(A), (B), (C), (F), (Q),
(T)], ATP-binding transporters [msr(A) and msr(D)], efflux
pumps [mef(A)] and transferases [lnu(C)].41,42 Two resistance
mechanism types account for almost all of the overall burden of
resistance (in terms of MIC values and prevalence) to macrolides in streptococci and are discussed in more detail below.

Review
been known for over 20 years that they act as a motilin receptor
agonist in the gut and gallbladder61,62 stimulating enteric nerves
and smooth muscle and triggering a phase of the migrating myoelectric complex.63,64 The antral motor effects of erythromycin
A in humans are mediated via different pathways. The induction
of a premature activity front is mediated through activation of an
intrinsic cholinergic pathway, while the induction of enhanced
antral contractile activity may be mediated via a pathway potentially involving activation of a muscular receptor.65 Different
doses of erythromycin A may have different effects as
suggested in studies in patients with diabetic gastroparesis.14
Forty mg erythromycin A elicited a premature phase 3 complex
that started in the stomach and migrated to the small intestine,
while doses of 200 and 350 mg erythromycin A elicited a burst
of antral phase-3-like contractions that did not migrate to the
small intestine, but were followed by a prolonged period of
antral contractile activity.

Over the last decade, pharmaceutical companies have been

investing significantly less in the development of new antimicrobial agents66 and we are currently facing a future where we will
rely upon conserving the useful activity of our existing agents
more than developing new agents in order to overcome or
control the problem of resistance emergence. Therefore questions as follows need to be answered:

What is the epidemiology of the emergence of

macrolide resistance?
There are many papers demonstrating that emergence of resistance to macrolides (which is often associated with co-resistance
to other antibiotics) appears to be closely correlated to macrolide
consumption.21 23,36,37,67,68 In the case of S. pneumoniae, links
with antibiotic use and resistance have been found at every
ecological level,36 from individual patients69 to different
geographical regions70 and countries.71 Overall consumption of
macrolides has been shown to vary significantly between
European countries. Studies done by the European Surveillance
of Antimicrobial Consumption (ESAC) Project Group,72 reveal
that total national macrolide use [expressed in defined daily
doses (DDD) per 1000 inhabitants per day] in 2003 was 0.85 in
Sweden compared with 9.36 in Greece. They also reveal that
macrolide consumption continues to increase in some countries
including Portugal, Ireland, Finland, Denmark and especially
Greece, where there has been a dramatic increase in total macrolide consumption from 4.16 DDD/1000 inhabitants/day in 1997
to 9.36 in 2003. Another study by the ESAC Project Group adds
further weight to the concerns over increasing antibiotic consumption and alarming resistance rates by showing a correlation
between antibiotic resistance and outpatient antibiotic use in
Europe.23 Clonality and related mechanisms of macrolide resistance in S. pneumoniae have been reported recently. The authors
observed that common clones are shared between Europe, Asia
and America, with clustering within countries.73 As demonstrated repeatedly, rates of resistance and phenotype vary widely
between geographical areas and are affected by many factors,
not all of which are fully understood. They include different

What is the evidence for conditions promoting bacterial

resistance against macrolides?
It is known that dose and therefore tissue levels achieved have
an effect on the ability of microorganisms to select for resistance under antibiotic pressure.67 Both the MLSB and M phenotypes have been described among pathogens such as S.
pneumoniae and S. pyogenes in addition to the viridans group
streptococci that comprise the normal oropharyngeal flora in
the healthy population. Also, further resistance mechanisms are
emerging a novel efflux system in S. pyogenes not associated
with mef(A) or other known macrolide efflux genes has been
described and found to be transferable between strains of
S. pyogenes.86
The viridans group streptococci are thought to play a significant role in the spread of macrolide resistance. Antibiotic
pressure with macrolides increases the prevalence of erythromycin-A-resistant viridans group streptococci; it is well known that
resistance rapidly emerges among oral streptococci in patients

350

Downloaded from http://jac.oxfordjournals.org/ by guest on December 17, 2016

Risk versus benefits

antibiotics exerting different selective powers23 and local spread

of resistant or susceptible clones, in addition to those factors
influencing antibiotic consumption, e.g. genetic, cultural, sociological and public health factors.36 Felmingham et al. found
rates of resistance to erythromycin A of up to 87.6% in S. pneumoniae in South Korea compared with 4.7% in Sweden.71 Other
studies demonstrate differences in the prevalence of phenotypes;
one study of invasive pneumococcal isolates in Germany25
revealed that 56.1% of macrolide-resistant isolates were of the
M phenotype (43.4% MLSB) compared with a Belgian study74
with 9.1% M phenotype macrolide-resistant S. pneumoniae isolates. Similar findings regarding the variance in resistance rates
and phenotypes have been found in isolates of S. pyogenes 75 78
and also in viridans group streptococci.24,50,51,79 81
In the past decade macrolide resistance has rapidly increased,
exceeding resistance rates to b-lactam antibiotics in some parts
of the world in the case of clinical S. pneumoniae isolates.82
National surveillance in Germany revealed an increase in erythromycin A resistance in pneumococcal isolates from 3.0% in
1992 to 15.3% in 2000, thought to be driven by uncritical usage
of macrolides. The authors warned that broad usage of macrolides ought to be reconsidered.25 Another American surveillance
study also concurred with the rapid increase in the numbers of
macrolide-resistant pneumococcal strains.83 However, a
Canadian surveillance study notes that their prevalence of
macrolide resistance in S. pneumoniae isolates has remained
stable at around 8% between 1997 and 2000 despite large
increases in macrolide consumption.84 This was thought to have
occurred secondary to the total use of antibiotics in Canada
decreasing over this period. There is controversy concerning the
clinical significance of in vitro macrolide resistance as few
patients with clinical failure have been reported.85 However, the
study by Gay et al.83 showed that the increase in high-level
macrolide resistance in Atlanta was almost exclusively of a mefmediated type, which was associated with higher MICs whereas
erm-mediated resistance remained stable. They postulate that
this may lead to an increase in clinical failures. Overall, studies
tend to suggest a correlation between macrolide resistance and
clinical failure,4 although further studies are needed to assess the
in vivo impact of in vitro resistance.

Review
resistance is likely to be fostered this way. However, the
anaerobic gut flora has been shown to participate in the
exchange and accumulation of genetic elements encoding for
erythromycin A resistance. In their survey, Shoemaker et al.
found that six strains of Bacteroides spp. had acquired an
erm(B) gene, which turned out almost identical to erm(B) from
Clostridium perfringens, S. pneumoniae and Enterococcus.101
Furthermore, an erythromycin A resistance gene from a conjugal
Bacteroides spp. transposon has been found to be almost
identical to erm(G) from Bacillus sphaericus, a Gram-positive
bacterium usually found in soil.102
Another topical concern has been the spread of a toxigenic
strain of Clostridium difficile PCR ribotype O27 particularly
affecting hospitals in North America and the UK.103 A recent
study into the rates of resistance to commonly used antibiotics
in clinical isolates of C. difficile from symptomatic hospital
patients has shown that resistance rates to erythromycin A were
as high as 98% and 100% for the two most commonly occurring
PCR ribotypes (001 and 006 respectively).104 There is an MLS
resistance gene designated erm(BZ) associated with toxigenic
C. difficile and transfer between C. difficile strains has been
demonstrated.105 The investigators found that the element
responsible for gene transfer was characteristic of a conjugative
transposon, was found in six C. difficile strains and could be
transferred to a non-toxigenic C. difficile strain demonstrating
that exposure of gut organisms to antibiotics not primarily
intended for their eradication promotes horizontal gene transfer.
Further evidence was found by researchers in the Netherlands
when investigating the sudden increase in multidrug-resistant
Enterobacteriaceae. They identified a number of integrons, one
of which also conferred erythromycin resistance. Conjugation
experiments supported the epidemiological evidence of horizontal transfer of resistance genes.106
Rice reviewed the same aspect for the Gram-positive bacteria
concluding that common Gram-positive pathogens are able to
associate and propagate antimicrobial resistance genes.107 When
evaluating the composition of a number of transposable genetic
elements, Rice also found compelling evidence that as a result
of high exposure to antimicrobials, bacteria are able to associate
insertion sequence elements with resistance genes thus generating novel integrative elements conferring resistance. Genomic
data suggest that this ancient ability proved to be an essential
tool for the bacterial evolutionary process.108 Therefore it can be
concluded that the extensive use of antibiotics in the clinical
setting is placing the bacterial community under selective
pressure resulting in the application of ancient evolutionary
tools in order to develop protective mechanisms for survival
under those circumstances. Recent research suggests that a
process called modular evolution may enable bacteria to retain
horizontally acquired genes even once they do not provide a
selective advantage anymore.109,110

What is the clinical role for prokinetics?

To date, the use of prokinetic agents for improvement of gastric
emptying has been investigated in a range of clinical settings
outside that of the critical care unit and these are beyond the
scope of this article.11,14 For example, erythromycin A shortened
the prolonged gastric-emptying times for both liquids and solids
to normal in patients with insulin-dependent diabetes mellitus
and gastroparesis suggesting that it may have therapeutic value

351

Downloaded from http://jac.oxfordjournals.org/ by guest on December 17, 2016

treated with erythromycin A87 and this effect appears to last at

least up to 8 weeks after the antibiotic pressure is removed.88
Rates of pharyngeal carriage of resistant commensal streptococci
are as high as 94.4% in a population comprising both healthy
subjects and those suffering pharyngitis.24 Worryingly, the intragenic transfer of macrolide-resistant determinants is possible89
and it is likely that genes such as erm and mef will spread into
new species.42 Transfer of genes coding for mechanisms of
resistance to macrolides has been demonstrated between isolates
of S. pyogenes 86,90 and between isolates of S. pneumoniae 48 and
from viridans group streptococci isolates to pathogenic isolates
such as S. pyogenes and S. pneumoniae. 91 The predominance of
the same resistance determinants found in both commensal bacteria and pathogens suggests the genetic transfer of resistance
determinants.51 Seppala et al.92 demonstrated that the distribution of phenotypes among the viridans streptococci resembles
that found in S. pyogenes, with predominance of the M phenotype and that the gene coding for the MLSB phenotype, erm(B),
is the same in viridans streptococci as in S. pneumoniae. These
results emphasize that these components of our oropharyngeal
flora may act as a reservoir of resistance genes by providing a
pool of resistant bacteria that may transfer resistance determinants to more pathogenic organisms.91 93
Emergence of macrolide resistance is not only limited to
streptococci. For example, it has been shown to arise during
eradication treatment of Helicobacter pylori from the stomach
mucosa,94 often in combination with another antimicrobial agent
and a proton pump inhibitor95 and seems to be secondary to
rRNA mutations.96 Consequently, the rate of macrolide resistance in H. pylori may cause therapeutic problems in the future.
Similar to the upper respiratory tract, the human colon has
long been demonstrated to be an ideal environment for both the
inter- and intra-species transfer of macrolide resistance. Twenty
years ago, the acquisition of the plasmid-mediated gene ere(A)
expressing an esterase leading to high-level resistance to erythromycin A in Escherichia coli had already been reported. Before
that, the organism only expressed low-level intrinsic resistance
to macrolides.60 In another study, the conjugative plasmid
pIP1100 encoding ampicillin and gentamicin resistance in
addition to erythromycin A resistance was isolated from the
blood of a patient treated with erythromycin.97 At the time, oral
erythromycin A was used for selective gut decontamination of
Enterobacteriaceae on the basis that the intraluminal concentrations achieved substantially exceeded the MICs of these
organisms. When investigating the epidemiological aspects of
using erythromycin A for selective gut decontamination, the
authors demonstrated that individual exposure to erythromycin,
rather than cross-infection, resulted in the emergence of
Enterobacteriaceae expressing high-level resistance to erythromycin.97 Later it could be demonstrated that the relevant genes,
ere(A) and ere(B), encoding for two distinct erythromycin A
esterases, and erm(AM), encoding for a rRNA methylase, were
already disseminated amongst other species of the
Enterobacteriaceae.98 A variant of ere(A) has been found in an
integron cassette of a multiresistant strain of Providencia.99 The
transferability of plasmid pIP1100 was also investigated in a
mouse model.100 The authors found in a gnotobiotic mice model
that transferability was antagonized in the presence of the
anaerobic flora of the human gut. This observation is of particular interest in respect of the intensive care setting where patients
often require anti-anaerobe chemotherapy, hence the transfer of

Review

What is the clinical evidence for erythromycin A as a

prokinetic agent?
So far there are no studies that have investigated the impact of
erythromycin A use upon clinical endpoints in critical care
patients. Two studies have shown that erythromycin A increases
the success rate of small-bowel-feeding-tube placement (and
shortens procedure time) compared with placebo,124,125 although
another study did not find any significant advantage of erythromycin A over metoclopramide in this setting and in fact concluded that motility agents given prior to tube insertion do not
augment advancement of the feeding tube beyond the stomach
and may in fact hinder placement into the duodenum.126
Booth et al. 18 found only two small studies in their review
investigating the effects of erythromycin A compared with
placebo on gastrointestinal transit and feeding tolerance with
sample populations ranging from 10 to 20.17,127 Their findings
suggested that erythromycin, when using acetaminophen as a
surrogate marker, increased its absorption and antral contractions, reduced residual volumes, did not have a significant effect
on gastric microbial overgrowth128 and was associated with
patients being categorized as successful feeders. However,
another larger placebo controlled trial of 40 consecutive patients

demonstrated that erythromycin A promoted gastric emptying

only for the first 3 days of enteral feeding but that it had no
significant effect on residual volumes after this time.129

What alternative prokinetic agents are available?

Erythromycin A is not the only agent with prokinetic properties.
A variety of agents have been considered and investigated for
use as prokinetics. Although alternative agents are limited, there
are some that are clinically available. Outlined below are some
of those that have been in clinical use or are being developed
for clinical use. Despite the paucity of published and robust
clinical trials, where possible, we have reviewed the current literature for evidence of each agents effectiveness within the
critical care setting and performance against erythromycin.
Metoclopramide. This drug promotes gastric emptying by acting
as an antagonist to the inhibitory actions of dopamine in the
gut.121 It also sensitizes the gut to acetylcholine and increases
the lower oesophageal sphincter tone.122 The review by Booth
et al. 18 concluded that administration of metoclopramide
appears to increase physiological indices of gastrointestinal
transit and feeding tolerance. As yet, there is no consensus upon
the appropriate dose to use and 20 mg appears to be no more
efficacious than 10 mg.122
Few placebo comparison studies have been done and those
that do exist are of small sample size. One crossover study of 10
patients comparing the effect of one dose of 10 mg intravenous
metoclopramide with intravenous saline upon the physiological
outcome of acetaminophen absorption concluded it improved
gastric emptying,130 as did the small study by Calcroft et al.131
Another similar study132 (eight patients, one dose via the nasogastric tube of each prokinetic and placebo per patient) found
10 mg metoclopramide via the nasogastric tube had no significant effect over placebo on mean residence time of acetaminophen absorption (the same was found with 200 mg erythromycin
A versus placebo), but did tend to accelerate absorption once it
had started to occur. They found erythromycin A did not have
this effect. In the context of usefulness of metoclopramide over
placebo in feeding tube placement, one small study using
20 mg iv133 concluded it aided placement when given prior to
tube insertion while studies using 10 mg iv126,134,135 concluded
it did not. Only one large randomized trial has assessed the
impact of prokinetic use in the critically ill on clinical outcomes
including incidence of pneumonia and mortality rate.123
Metoclopramide (10 mg given via a nasogastric tube) was the
only drug studied and it did not show any clinical benefit over
placebo.
We have found two studies on critically ill patients that
include both metoclopramide and erythromycin. The MacLaren
study132 above found that metoclopramide was significantly
better at shortening the mean residence time for acetaminophen
absorption and also for accelerating gastric emptying in critically
ill patients and a larger, methodologically robust study found
that neither metoclopramide nor erythromycin A augment the
advancement of a feeding tube beyond the stomach.126
Lastly, as part of their review into nutrition support in
mechanically ventilated, critically ill adult patients, the
Canadian Critical Care Practice Guidelines Committee have recommended that given the low probability of harm and favourable feasibility, motility agents may be considered to optimize

352

Downloaded from http://jac.oxfordjournals.org/ by guest on December 17, 2016

in patients with severe diabetic gastroparesis.11,14 It has also

shown potential benefit in other areas, including patients after
vagotomy111 and patients with chronic intestinal pseudoobstruction.112
One area where this application could have a particular
impact is in the critical care setting. Successful and early administration of enteral nutrition is integral to improving clinical
outcome; resulting in fewer septic complications, decreased bacterial gut translocation and catabolic response to injury and
improved wound healing.113 115 However, numerous studies
evaluating gastrointestinal motility by measuring acetaminophen
absorption and performing manometry and breath testing have
shown that this is frequently impaired in the critically ill, with
decreased gastric emptying and diminished migrating motor
complexes.116 119 Slow gastric emptying, or gastroparesis, is a
major limitation in mechanically ventilated patients and, in
addition to impairing the absorption of nutrients and drugs, can
lead to complications directly related to enteral feeding, such as
bacterial overgrowth and oesophageal reflux. Such complications
place these patients at risk of pulmonary aspiration, pneumonia
and sepsis, which in turn impacts on mortality.120 Prokinetic
agents may improve tolerance to enteral nutrition by overcoming
gastrointestinal dysmotility.115,121 Their usefulness in the critical
care population has been reviewed.18,122 This class of drugs
(which includes the non-antibiotics in addition to erythromycin)
was found to have a beneficial effect on gastrointestinal motility as measured by endpoints such as gastric residuals, acetaminophen absorption as a surrogate marker and manometry in
certain situations during enteral feeding. However, it is recognized that the number and sample sizes of clinical trials in
this area are small and that finer details such as the ideal doses
of the drugs are yet to be established. Only one randomized
trial of motility agents to date has assessed their impact on
clinical outcomes including incidence of pneumonia and mortality rate123 and it did not show any benefit of the prokinetic
over placebo.

Review
nutritional intake.136 They suggest that because of concerns of
bacterial resistance with erythromycin, metoclopramide should
be used.

Tegaserod. Tegaserod is a selective serotonin type 4 receptor

partial agonist. The activation of the 5-hydroxytryptamine4
(5-HT4) receptors results in the activation of the peristaltic reflex
and an increase in intestinal secretions.142 It is licensed in
Canada for the relief of irritable bowel syndrome symptoms
such as constipation, abdominal pain and bloating. It is not currently in use in the UK. No studies have been published,
although there are case reports of its successful use in intensive
care patients with impaired gastric motility.143 Further studies
are needed.
Cisapride. Promotes motility by activating 5-HT4 receptors, thus
enhancing acetylcholine release in the enteric plexus121 and
initiating the gastric peristaltic reflex. It has been found to accelerate gastric emptying as assessed by acetaminophen absorption
in patients with idiopathic and diabetic gastroparesis144,145 and
also in critically ill patients.146,147 It was withdrawn from the
market in the UK in May 2000 over concerns regarding cardiac
dysrhythmias.
Motilin receptor agonists motilides (ABT-229). ABT-229 is a
specific motilin agonist that dose-dependently accelerates gastric
emptying.148 It has been studied in patients with functional dyspepsia and diabetic gastroparesis,148,149 but results so far have
been disappointing with no significant symptom improvement
seen.150 Drug factors such as tachyphylaxis may have played a
role in therapeutic failure.

Conclusions
We find that today we live in a world where there are already
areas with a high prevalence of erythromycin A resistance
within our populations; whether that is the healthy adult

353

Downloaded from http://jac.oxfordjournals.org/ by guest on December 17, 2016

Domperidone. Like metoclopramide, this drug is another dopamine receptor antagonist, mediating the inhibitory action of
dopamine on the upper gastrointestinal tract. However, it is a
chemically distinct dopamine2-antagonist and unlike metoclopramide it acts peripherally.137 The clinical role of domperidone in
critically ill patients with gastrointestinal dysmotility has not
been established and there are no published studies. It has
however been extensively studied138 in other clinical scenarios
such as diabetic gastroparesis,139 functional dyspepsia140,141 and
gastro-oesophageal reflux disease (GORD).141 A review of the
literature on the effect of domperidone on symptomatic response
to treatment found that domperidone provided better relief from
symptoms than placebo and was comparable to metoclopramide
in patients with diabetic gastropathy and dyspepsia and promising outcomes were also seen in trials reviewing GORD.138 The
same reviewer noted that as, unlike metoclopramide, domperidone does not readily cross the blood brain barrier, it is less
likely to cause the central nervous system adverse effects (e.g.
dystonic reactions and dizziness) seen occasionally with metoclopramide. Therefore it may become a useful therapeutic
alternative to other prokinetic agents in critical illness. Further
studies are needed.

population (with a study finding oropharyngeal carriage rates of

70% in Belgium51 and another finding rates of 94% in Spain24)
or in organisms regarded as pathogens. In view of this, and
the decline in the development of novel antimicrobial agents,
the decision of which clinical situations it is appropriate to use
antibiotics in becomes critical. We agree with Goossens et al. in
that the ethics of promoting antibiotics in clinical situations in
which they are unnecessary should be given serious
consideration.23
The use of erythromycin A at doses far below the concentrations necessary for an inhibitory effect on susceptible bacteria
provides close to ideal conditions for the induction of bacterial
mutation and selection,151,152 which is the type of situation
achieved at some of the doses of erythromycin A proposed for
use as a prokinetic.17,22,124,126,127
We already know that increased antibiotic pressure can create
an environment suitable for the emergence of macrolide resistance and that it is potentially possible for resistance genes
associated with mobile genetic elements to facilitate spread of
resistance in oropharyngeal flora and among invasive clinical
isolates. These factors are especially important when applied to
the closed environment of the critical care unit, where resistant
organisms have the ability to become resident153 or cause outbreaks,154,155 posing a risk to patients on the unit.
In the critically ill population prokinetics have been proposed
to have a beneficial effect. However, the evidence so far is
based on a small number of studies, which importantly have not
been able to consistently concur on doses and length of time
needed for optimum prokinetic effect and include few on actual
clinical outcome measures. Indeed, some studies (including the
one measuring clinical endpoints) are conflicting and unable to
prove that prokinetics even have a significant beneficial effect,
although this may be because larger studies are needed.
The evidence for the use of macrolides such as erythromycin
A as a first-line treatment of a non-septic condition such as gastrointestinal dysmotility in the critical care population is weak.
In fact, the American Society for Parenteral and Enteral
Nutrition (ASPEN) states explicitly that, because of the concerns
about the emergence of bacterial resistance, only metoclopramide should be used.136 In their recent guidelines, the European
Society for Clinical Nutrition and Metabolism (ESPEN) goes
even further by not recommending the use of erythromycin A or
another prokinetic agents at all.156
On balance, we conclude that current evidence is not complete enough to be able to state that one prokinetic agent, e.g.
erythromycin, is superior to another, e.g. metoclopramide, in the
critical care setting.18,130,132,157 In view of this, the use of erythromycin A as a first-line agent for the treatment of gastric dysmotility in the critically ill lacks sufficient data to justify taking
the risks of promoting the spread of macrolide resistance. Owing
to the growing weight of evidence illustrating the potential epidemiological impact of increased and wider usage of erythromycin A and its fellow macrolides upon both the emergence of
antibiotic resistance and its genetic determinants ability to
transfer and collect within the bacterial flora of both patients and
healthy individuals in the general population, we are of the
opinion that the use of erythromycin A as a prokinetic agent in
the critical care unit should be restricted to only those patients
who have already failed all other treatments for impaired gastric
motility and are intolerant of a first-line agent such as metoclopramide. In our own hospital there is an agreement within the

Review
Intensive Care Team that erythromycin A should only be used
as a prokinetic in exceptional circumstances.

Acknowledgements
We are indebted to our colleague Paul McAndrew for his
encouragements, his valuable suggestions and for critically
reviewing the manuscript. We also would like to thank the two
anonymous reviewers for their helpful suggestions.

Transparency declarations
None to declare.

References

354

Downloaded from http://jac.oxfordjournals.org/ by guest on December 17, 2016

1. Bryskier A, Butzler JP. Macrolides. In: Finch RG, Greenwood D,

Norrby SR et al., eds. Antibiotic and Chemotherapy. Anti-Infective
Agents and Their Use in Therapy. 8th edn. Edinburgh: Churchill
Livingstone, 2003; 310 37.
2. Sivapalasingham S, Steigbigel NH. Macrolides, clindamycin,
and ketolides. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and
Practice of Infectious Diseases. 6th edn. Philadelphia: Elsevier
Churchill Livingstone, 2005; 396.
3. McGuire JM, Bunch RL, Anderson RC et al. Ilotycin, a new
antibiotic. Schweiz Med Wochenschr 1952; 82: 1064 5.
4. Leclercq R. Mechanisms of resistance to macrolides and lincosamides: nature of the resistance elements and their clinical implications. Clin Infect Dis 2002; 34: 482 92.
5. Bryskier A. Ketolidestelithromycin, an example of a new
class of antibacterial agents. Clin Microbiol Infect 2000; 6: 661 9.
6. Labro MT. Anti-inflammatory activity of macrolides: a new therapeutic potential? J Antimicrob Chemother 1998; 41 Suppl B: 3746.
7. Schultz MJ. Macrolide activities beyond their antimicrobial
effects: macrolides in diffuse panbronchiolitis and cystic fibrosis.
J Antimicrob Chemother 2004; 54: 218.
8. Amsden GW. Anti-inflammatory effects of macrolidesan
underappreciated benefit in the treatment of community-acquired respiratory tract infections and chronic inflammatory pulmonary conditions? J Antimicrob Chemother 2005; 55: 10 21.
9. Tamaoki J, Kadota J, Takizawa H. Clinical implications of the
immunomodulatory effects of macrolides. Am J Med 2004; 117 Suppl
9A: 5S 11S.
10. Siddiqui J. Immunomodulatory effects of macrolides: implications for practicing clinicians. Am J Med 2004; 117 Suppl 9A:
26S29S.
11. Janssens J, Peeters TL, Vantrappen G et al. Improvement of
gastric emptying in diabetic gastroparesis by erythromycin. Preliminary
studies. N Engl J Med 1990; 322: 1028 31.
12. Ramirez B, Richter JE. Review article: promotility drugs in the
treatment of gastro-oesophageal reflux disease. Aliment Pharmacol
Ther 1993; 7: 520.
13. Chicella MF, Batres LA, Heesters MS et al. Prokinetic drug
therapy in children: a review of current options. Ann Pharmacother
2005; 39: 70611.
14. Tack J, Janssens J, Vantrappen G et al. Effect of erythromycin
on gastric motility in controls and in diabetic gastroparesis.
Gastroenterology 1992; 103: 729.
15. Arts J, Caenepeel P, Verbeke K et al. Influence of erythromycin
on gastric emptying and meal related symptoms in functional dyspepsia with delayed gastric emptying. Gut 2005; 54: 455 60.

16. Bortolotti M, Mari C, Brunelli F et al. Effect of intravenous

clarithromycin on interdigestive gastroduodenal motility of patients with
functional dyspepsia and Helicobacter pylori gastritis. Dig Dis Sci 1999;
44: 243942.
17. Chapman MJ, Fraser RJ, Kluger MT et al. Erythromycin
improves gastric emptying in critically ill patients intolerant of nasogastric feeding. Crit Care Med 2000; 28: 23347.
18. Booth CM, Heyland DK, Paterson WG. Gastrointestinal promotility drugs in the critical care setting: a systematic review of the evidence. Crit Care Med 2002; 30: 142935.
19. Stroud M, Duncan H, Nightingale J. Guidelines for enteral
feeding in adult hospital patients. Gut 2003; 52 Suppl 7: vii112.
20. Mutlu GM, Mutlu EA, Factor P. GI complications in patients
receiving mechanical ventilation. Chest 2001; 119: 122241.
21. Granizo JJ, Aguilar L, Casal J et al. Streptococcus pyogenes
resistance to erythromycin in relation to macrolide consumption in
Spain (19861997). J Antimicrob Chemother 2000; 46: 95964.
22. Granizo JJ, Aguilar L, Casal J et al. Streptococcus pneumoniae
resistance to erythromycin and penicillin in relation to macrolide and
b-lactam consumption in Spain (19791997). J Antimicrob Chemother
2000; 46: 76773.
23. Goossens H, Ferech M, Vander Stichele R et al. Outpatient
antibiotic use in Europe and association with resistance: a crossnational database study. Lancet 2005; 365: 57987.
24. Perez-Trallero E, Vicente D, Montes M et al. High proportion of
pharyngeal carriers of commensal streptococci resistant to erythromycin in Spanish adults. J Antimicrob Chemother 2001; 48: 2259.
25. Reinert RR, Al-Lahham A, Lemperle M et al. Emergence of
macrolide and penicillin resistance among invasive pneumococcal isolates in Germany. J Antimicrob Chemother 2002; 49: 61 8.
26. Seppala H, Nissinen A, Yu Q et al. Three different phenotypes
of erythromycin-resistant Streptococcus pyogenes in Finland. J
Antimicrob Chemother 1993; 32: 88591.
27. Chittum HS, Champney WS. Erythromycin inhibits the assembly of the large ribosomal subunit in growing Escherichia coli cells.
Curr Microbiol 1995; 30: 2739.
28. Pestka S. Insights into protein biosynthesis and ribosome function through inhibitors. Prog Nucleic Acid Res Mol Biol 1976; 17:
21745.
29. Jenkins G, Zalacain M, Cundliffe E. Inducible ribosomal RNA
methylation in Streptomyces lividans, conferring resistance to lincomycin. J Gen Microbiol 1989; 135: 32818.
30. Birmingham VA, Cox KL, Larson JL et al. Cloning and
expression of a tylosin resistance gene from a tylosin-producing strain
of Streptomyces fradiae. Mol Gen Genet 1986; 204: 5329.
31. Fouces R, Mellado E, Diez B et al. The tylosin biosynthetic
cluster from Streptomyces fradiae: genetic organization of the left
region. Microbiology 1999; 145: 85568.
32. Gaynor M, Mankin AS. Macrolide antibiotics: binding site,
mechanism of action, resistance. Curr Top Med Chem 2003; 3:
94961.
33. British Thoracic Society Standards of Care Committee. BTS
guidelines for the management of community acquired pneumonia in
adults. Thorax 2001; 56 Suppl 4: IV164.
34. Cooper RJ, Hoffman JR, Bartlett JG et al. Principles of appropriate antibiotic use for acute pharyngitis in adults: background. Ann
Intern Med 2001; 134: 50917.
35. Douthwaite S, Champney WS. Structures of ketolides and
macrolides determine their mode of interaction with the ribosomal
target site. J Antimicrob Chemother 2001; 48 Suppl T1: 18.
36. Baquero F, Baquero-Artigao G, Canton R et al. Antibiotic
consumption and resistance selection in Streptococcus pneumoniae.
J Antimicrob Chemother 2002; 50 Suppl S2: 27 37.

Review
56. Canton R, Mazzariol A, Morosini MI et al. Telithromycin activity
is reduced by efflux in Streptococcus pyogenes. J Antimicrob
Chemother 2005; 55: 48995.
57. Weisblum B. Erythromycin resistance by ribosome modification.
Antimicrob Agents Chemother 1995; 39: 57785.
58. Cundliffe E. How antibiotic-producing organisms avoid suicide.
Annu Rev Microbiol 1989; 43: 20733.
59. Tamayo J, Perez-Trallero E, Gomez-Garces JL et al.
Resistance to macrolides, clindamycin and telithromycin in
Streptococcus pyogenes isolated in Spain during 2004. J Antimicrob
Chemother 2005; 56: 7802.
60. Ounissi H, Courvalin P. Nucleotide sequence of the gene ereA
encoding the erythromycin esterase in Escherichia coli. Gene 1985;
35: 2718.
61. Itoh Z, Suzuki T, Nakaya M et al. Gastrointestinal motorstimulating activity of macrolide antibiotics and analysis of their side
effects on the canine gut. Antimicrob Agents Chemother 1984; 26:
863 9.
62. Itoh Z, Suzuki T, Nakaya M et al. Structure-activity relation
among macrolide antibiotics in initiation of interdigestive migrating contractions in the canine gastrointestinal tract. Am J Physiol 1985; 248:
G3205.
63. Peeters TL. Erythromycin and other macrolides as prokinetic
agents. Gastroenterology 1993; 105: 188699.
64. Miller P, Roy A, St-Pierre S et al. Motilin receptors in the
human antrum. Am J Physiol Gastrointest Liver Physiol 2000; 278:
G1823.
65. Coulie B, Tack J, Peeters T et al. Involvement of two different
pathways in the motor effects of erythromycin on the gastric antrum in
humans. Gut 1998; 43: 395400.
66. Spellberg B, Powers JH, Brass EP et al. Trends in antimicrobial
drug development: implications for the future. Clin Infect Dis 2004; 38:
127986.
67. Kastner U, Guggenbichler JP. Influence of macrolide antibiotics
on promotion of resistance in the oral flora of children. Infection 2001;
29: 2516.
68. Huovinen P, Seppala H, Kataja J et al. The relationship
between erythromycin consumption and resistance in Finland. Finnish
Study Group for Antimicrobial Resistance. Ciba Found Symp 1997;
207: 36 41; discussion 416.
69. del Castillo F, Baquero-Artigao F, Garcia-Perea A. Influence of
recent antibiotic therapy on antimicrobial resistance of Streptococcus
pneumoniae in children with acute otitis media in Spain. Pediatr Infect
Dis J 1998; 17: 94 7.
70. Garcia-Rey C, Aguilar L, Baquero F et al. Importance of local
variations in antibiotic consumption and geographical differences of
erythromycin and penicillin resistance in Streptococcus pneumoniae. J
Clin Microbiol 2002; 40: 15964.
71. Felmingham D, Reinert RR, Hirakata Y et al. Increasing prevalence of antimicrobial resistance among isolates of Streptococcus
pneumoniae from the PROTEKT surveillance study, and comparative
in vitro activity of the ketolide, telithromycin. J Antimicrob Chemother
2002; 50 Suppl S1: 2537.
72. Coenen SFM, Malhotra-Kumar S, Hendrickx E et al. European
Surveillance of Antimicrobial Consumption. Outpatient macrolide, lincosamide and streptogramin (MLS) use in Europe, 2006. http://www.
esac.ua.ac.be/main.aspx?c=*ESAC2&n=24345 (15 Aug 2006, date last
accessed).
73. Bozdogan B, Bogdanovich T, Kosowska K et al. Macrolide
resistance in Streptococcus pneumoniae: clonality and mechanisms of
resistance in 24 countries. Curr Drug Targets Infect Disord 2004; 4:
169 76.
74. Descheemaeker P, Chapelle S, Lammens C et al. Macrolide
resistance and erythromycin resistance determinants among Belgian

355

Downloaded from http://jac.oxfordjournals.org/ by guest on December 17, 2016

37. Dias R, Canica M. Emergence of invasive erythromycinresistant Streptococcus pneumoniae strains in Portugal: contribution
and phylogenetic relatedness of serotype 14. J Antimicrob Chemother
2004; 54: 10359.
38. Kristinsson KG. Modification of prescribers behavior: the
Icelandic approach. Clin Microbiol Infect 1999; 5 Suppl 4: S437.
39. Giovanetti E, Brenciani A, Lupidi R et al. Presence of the
tet(O) gene in erythromycin- and tetracycline-resistant strains of
Streptococcus pyogenes and linkage with either the mef(A) or the
erm(A) gene. Antimicrob Agents Chemother 2003; 47: 28449.
40. Sutcliffe J, Tait-Kamradt A, Wondrack L. Streptococcus
pneumoniae and Streptococcus pyogenes resistant to macrolides but
sensitive to clindamycin: a common resistance pattern mediated by
an efflux system. Antimicrob Agents Chemother 1996; 40: 1817 24.
41. Roberts MC. Table 4. Location of the various genes. http://
faculty.washington.edu/marilynr/ermweb4.pdf, 2006 (15 August 2006,
date last accessed).
42. Roberts MC, Sutcliffe J, Courvalin P et al. Nomenclature for
macrolide and macrolide-lincosamide-streptogramin B resistance determinants. Antimicrob Agents Chemother 1999; 43: 282330.
43. Poole K. Efflux-mediated antimicrobial resistance. J Antimicrob
Chemother 2005; 56: 20 51.
44. Clancy J, Petitpas J, Dib-Hajj F et al. Molecular cloning and
functional analysis of a novel macrolide-resistance determinant, mefA,
from Streptococcus pyogenes. Mol Microbiol 1996; 22: 86779.
45. Tait-Kamradt A, Clancy J, Cronan M et al. mefE is necessary
for the erythromycin-resistant M phenotype in Streptococcus pneumoniae. Antimicrob Agents Chemother 1997; 41: 22515.
46. Sutcliffe J, Grebe T, Tait-Kamradt A et al. Detection of
erythromycin-resistant determinants by PCR. Antimicrob Agents
Chemother 1996; 40: 2562 6.
47. Gay K, Stephens DS. Structure and dissemination of a chromosomal insertion element encoding macrolide efflux in Streptococcus
pneumoniae. J Infect Dis 2001; 184: 56 65.
48. Santagati M, Iannelli F, Oggioni MR et al. Characterization of a
genetic element carrying the macrolide efflux gene mef(A) in
Streptococcus pneumoniae. Antimicrob Agents Chemother 2000; 44:
25857.
49. Klaassen CH, Mouton JW. Molecular detection of the macrolide
efflux gene: to discriminate or not to discriminate between mef(A) and
mef(E). Antimicrob Agents Chemother 2005; 49: 1271 8.
50. Rodriguez-Avial I, Rodriguez-Avial C, Culebras E et al.
Distribution of mef(A) and erm(B) genes in macrolide-resistant blood
isolates of viridans group streptococci. J Antimicrob Chemother 2001;
47: 7278.
51. Malhotra-Kumar S, Lammens C, Martel A et al. Oropharyngeal
carriage of macrolide-resistant viridans group streptococci: a prevalence study among healthy adults in Belgium. J Antimicrob Chemother
2004; 53: 2716.
52. Cochetti I, Vecchi M, Mingoia M et al. Molecular characterization of pneumococci with efflux-mediated erythromycin resistance and
identification of a novel mef gene subclass, mef(I). Antimicrob Agents
Chemother 2005; 49: 4999 5006.
53. Kataja J, Huovinen P, Seppala H. Erythromycin resistance
genes in group A streptococci of different geographical origins. The
Macrolide Resistance Study Group. J Antimicrob Chemother 2000; 46:
78992.
54. McGee L, Klugman KP, Wasas A et al. Serotype 19F multiresistant pneumococcal clone harboring two erythromycin resistance
determinants [erm(B) and mef(A)] in South Africa. Antimicrob Agents
Chemother 2001; 45: 1595 8.
55. Sangvik M, Littauer P, Simonsen GS et al. mef(A), mef(E) and
a new mef allele in macrolide-resistant Streptococcus spp. isolates
from Norway. J Antimicrob Chemother 2005; 56: 841 6.

Review
91. Cerda Zolezzi P, Laplana LM, Calvo CR et al. Molecular basis
of resistance to macrolides and other antibiotics in commensal viridans
group streptococci and Gemella spp. and transfer of resistance genes
to Streptococcus pneumoniae. Antimicrob Agents Chemother 2004;
48: 34627.
92. Seppala H, Haanpera M, Al-Juhaish M et al. Antimicrobial susceptibility patterns and macrolide resistance genes of viridans group
streptococci from normal flora. J Antimicrob Chemother 2003; 52:
63644.
93. Ergin A, Ercis S, Hascelik G. Macrolide resistance mechanisms
and in vitro susceptibility patterns of viridans group streptococci isolated from blood cultures. J Antimicrob Chemother 2006; 57: 13941.
94. Versalovic J, Shortridge D, Kibler K et al. Mutations in 23S
rRNA are associated with clarithromycin resistance in Helicobacter
pylori. Antimicrob Agents Chemother 1996; 40: 47780.
95. Peitz U, Hackelsberger A, Malfertheiner P. A practical approach
to patients with refractory Helicobacter pylori infection, or who are
re-infected after standard therapy. Drugs 1999; 57: 90520.
96. Vester B, Douthwaite S. Macrolide resistance conferred by
base substitutions in 23S rRNA. Antimicrob Agents Chemother 2001;
45: 112.
97. Andremont A, Sancho-Garnier H, Tancrede C. Epidemiology of
intestinal colonization by members of the family Enterobacteriaceae
highly resistant to erythromycin in a hematology-oncology unit.
Antimicrob Agents Chemother 1986; 29: 11047.
98. Arthur M, Andremont A, Courvalin P. Distribution of erythromycin esterase and rRNA methylase genes in members of the family
Enterobacteriaceae highly resistant to erythromycin. Antimicrob Agents
Chemother 1987; 31: 4049.
99. Plante I, Centron D, Roy PH. An integron cassette encoding
erythromycin esterase, ere(A), from Providencia stuartii. J Antimicrob
Chemother 2003; 51: 78790.
100. Andremont A, Gerbaud G, Tancrede C et al. Plasmid-mediated
susceptibility to intestinal microbial antagonisms in Escherichia coli.
Infect Immun 1985; 49: 7515.
101. Shoemaker NB, Vlamakis H, Hayes K et al. Evidence for extensive resistance gene transfer among Bacteroides spp. and among
Bacteroides and other genera in the human colon. Appl Environ
Microbiol 2001; 67: 5618.
102. Cooper AJ, Shoemaker NB, Salyers AA. The erythromycin
resistance gene from the Bacteroides conjugal transposon Tcr Emr
7853 is nearly identical to ermG from Bacillus sphaericus. Antimicrob
Agents Chemother 1996; 40: 5068.
103. Warny M, Pepin J, Fang A et al. Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe
disease in North America and Europe. Lancet 2005; 366: 107984.
104. John R, Brazier JS. Antimicrobial susceptibility of polymerase
chain reaction ribotypes of Clostridium difficile commonly isolated from
symptomatic hospital patients in the UK. J Hosp Infect 2005; 61: 114.
105. Mullany P, Wilks M, Tabaqchali S. Transfer of
macrolide-lincosamide-streptogramin B (MLS) resistance in Clostridium
difficile is linked to a gene homologous with toxin A and is mediated by
a conjugative transposon, Tn5398. J Antimicrob Chemother 1995; 35:
30515.
106. Leverstein-van Hall MA, Box AT, Blok HE et al. Evidence of
extensive interspecies transfer of integron-mediated antimicrobial
resistance genes among multidrug-resistant Enterobacteriaceae in a
clinical setting. J Infect Dis 2002; 186: 4956.
107. Rice LB. Bacterial monopolists: the bundling and dissemination
of antimicrobial resistance genes in gram-positive bacteria. Clin Infect
Dis 2000; 31: 762 9.
108. Rice LB. Association of different mobile elements to generate
novel integrative elements. Cell Mol Life Sci 2002; 59: 202332.

356

Downloaded from http://jac.oxfordjournals.org/ by guest on December 17, 2016

Streptococcus pyogenes and Streptococcus pneumoniae isolates.

J Antimicrob Chemother 2000; 45: 167 73.
75. Alos JI, Aracil B, Oteo J et al. High prevalence of erythromycinresistant,
clindamycin/miocamycin-susceptible
(M
phenotype)
Streptococcus pyogenes: results of a Spanish multicentre study in
1998. Spanish Group for the Study of Infection in the Primary Health
Care Setting. J Antimicrob Chemother 2000; 45: 605 9.
76. Seppala H, Klaukka T, Vuopio-Varkila J et al. The effect of
changes in the consumption of macrolide antibiotics on erythromycin
resistance in group A streptococci in Finland. Finnish Study Group for
Antimicrobial Resistance. N Engl J Med 1997; 337: 441 6.
77. Jasir A, Schalen C. Survey of macrolide resistance phenotypes
in Swedish clinical isolates of Streptococcus pyogenes. J Antimicrob
Chemother 1998; 41: 135 7.
78. Klugman KP, Capper T, Widdowson CA et al. Increased activity
of 16-membered lactone ring macrolides against erythromycin-resistant
Streptococcus pyogenes and Streptococcus pneumoniae: characterization of South African isolates. J Antimicrob Chemother 1998; 42:
72934.
79. Arpin C, Canron MH, Maugein J et al. Incidence of mefA and
mefE genes in viridans group streptococci. Antimicrob Agents
Chemother 1999; 43: 2335 6.
80. Aracil B, Minambres M, Oteo J et al. High prevalence of
erythromycin-resistant and clindamycin-susceptible (M phenotype) viridans group streptococci from pharyngeal samples: a reservoir of mef
genes in commensal bacteria. J Antimicrob Chemother 2001; 48:
5924.
81. Uh Y, Shin DH, Jang IH et al. Antimicrobial susceptibility patterns and macrolide resistance genes of viridans group streptococci
from blood cultures in Korea. J Antimicrob Chemother 2004; 53:
10957.
82. Schito GC, Debbia EA, Marchese A. The evolving threat of
antibiotic resistance in Europe: new data from the Alexander Project.
J Antimicrob Chemother 2000; 46 Suppl T1: 3 9.
83. Gay K, Baughman W, Miller Y et al. The emergence of
Streptococcus pneumoniae resistant to macrolide antimicrobial agents:
a 6-year population-based assessment. J Infect Dis 2000; 182:
141724.
84. Hoban DJ, Wierzbowski AK, Nichol K et al. Macrolide-resistant
Streptococcus pneumoniae in Canada during 1998 1999: prevalence
of mef(A) and erm(B) and susceptibilities to ketolides. Antimicrob
Agents Chemother 2001; 45: 2147 50.
85. Amsden GW. Pneumococcal macrolide resistancemyth or
reality? J Antimicrob Chemother 1999; 44: 1 6.
86. Giovanetti E, Brenciani A, Burioni R et al. A novel efflux system
in inducibly erythromycin-resistant strains of Streptococcus pyogenes.
Antimicrob Agents Chemother 2002; 46: 3750 5.
87. King A, Bathgate T, Phillips I. Erythromycin susceptibility of
viridans streptococci from the normal throat flora of patients treated
with azithromycin or clarithromycin. Clin Microbiol Infect 2002; 8:
85 92.
88. Berg HF, Tjhie JH, Scheffer GJ et al. Emergence and persistence of macrolide resistance in oropharyngeal flora and elimination
of nasal carriage of Staphylococcus aureus after therapy with slowrelease clarithromycin: a randomized, double-blind, placebo-controlled
study. Antimicrob Agents Chemother 2004; 48: 4183 8.
89. Brisson-Noel A, Arthur M, Courvalin P. Evidence for natural
gene transfer from gram-positive cocci to Escherichia coli. J Bacteriol
1988; 170: 173945.
90. Giovanetti E, Magi G, Brenciani A et al. Conjugative transfer of
the erm(A) gene from erythromycin-resistant Streptococcus pyogenes
to macrolide-susceptible S. pyogenes, Enterococcus faecalis and
Listeria innocua. J Antimicrob Chemother 2002; 50: 249 52.

Review
132. MacLaren R, Kuhl DA, Gervasio JM et al. Sequential single
doses of cisapride, erythromycin, and metoclopramide in critically ill
patients intolerant to enteral nutrition: a randomized, placebocontrolled, crossover study. Crit Care Med 2000; 28: 43844.
133. Whatley K, Turner WW Jr, Dey M et al. When does metoclopramide facilitate transpyloric intubation? JPEN J Parenter Enteral Nutr
1984; 8: 679 81.
134. Heiselman DE, Hofer T, Vidovich RR. Enteral feeding tube
placement success with intravenous metoclopramide administration in
ICU patients. Chest 1995; 107: 16868.
135. Luchtefeld W, Shapiro M, Durham R et al. Efficacy of metoclopramide in facilitating duodenal placement of small bore feeding tubes
in trauma patients. JPEN J Parenter Enteral Nutr 1994; 18: 31S.
136. Heyland DK, Dhaliwal R, Drover JW et al. Canadian clinical
practice guidelines for nutrition support in mechanically ventilated, critically ill adult patients. JPEN J Parenter Enteral Nutr 2003; 27:
355 73.
137. Longo WE, Vernava AM III. Prokinetic agents for lower gastrointestinal motility disorders. Dis Colon Rectum 1993; 36: 696 708.
138. Barone
JA.
Domperidone:
a
peripherally
acting
dopamine2-receptor antagonist. Ann Pharmacother 1999; 33: 42940.
139. Horowitz M, Su YC, Rayner CK et al. Gastroparesis: prevalence, clinical significance and treatment. Can J Gastroenterol 2001;
15: 80513.
140. Veldhuyzen van Zanten SJ, Jones MJ, Verlinden M et al.
Efficacy of cisapride and domperidone in functional (nonulcer) dyspepsia: a meta-analysis. Am J Gastroenterol 2001; 96: 68996.
141. Halter F, Staub P, Hammer B et al. Study with two prokinetics
in functional dyspepsia and GORD: domperidone vs. cisapride. J
Physiol Pharmacol 1997; 48: 18592.
142. Mader R, Kocher T, Haier J et al. Investigation of serotonin
type 4 receptor expression in human and non-human primate gastrointestinal samples. Eur J Gastroenterol Hepatol 2006; 18: 94550.
143. Banh HL, MacLean C, Topp T et al. The use of tegaserod in
critically ill patients with impaired gastric motility. Clin Pharmacol Ther
2005; 77: 5836.
144. Richards RD, Valenzuela GA, Davenport KG et al. Objective
and subjective results of a randomized, double-blind, placebocontrolled trial using cisapride to treat gastroparesis. Dig Dis Sci 1993;
38: 8116.
145. Horowitz M, Maddern GJ, Maddox A et al. Effects of cisapride
on gastric and esophageal emptying in progressive systemic sclerosis.
Gastroenterology 1987; 93: 3115.
146. Heyland DK, Tougas G, Cook DJ et al. Cisapride improves
gastric emptying in mechanically ventilated, critically ill patients. A randomized, double-blind trial. Am J Respir Crit Care Med 1996; 154:
167883.
147. Spapen HD, Duinslaeger L, Diltoer M et al. Gastric emptying in
critically ill patients is accelerated by adding cisapride to a standard
enteral feeding protocol: results of a prospective, randomized, controlled trial. Crit Care Med 1995; 23: 4815.
148. Talley NJ, Verlinden M, Geenen DJ et al. Effects of a motilin
receptor agonist (ABT-229) on upper gastrointestinal symptoms in type
1 diabetes mellitus: a randomised, double blind, placebo controlled
trial. Gut 2001; 49: 395401.
149. Tack J, Peeters T. What comes after macrolides and other
motilin stimulants? Gut 2001; 49: 3178.
150. Talley NJ, Verlinden M, Snape W et al. Failure of a motilin
receptor agonist (ABT-229) to relieve the symptoms of functional dyspepsia in patients with and without delayed gastric emptying: a randomized double-blind placebo-controlled trial. Aliment Pharmacol Ther
2000; 14: 165361.
151. Guerin JM, Leibinger F. Why not to use erythromycin in GI
motility. Chest 2002; 121: 3012.

357

Downloaded from http://jac.oxfordjournals.org/ by guest on December 17, 2016

109. Rainey PB, Cooper TF. Evolution of bacterial diversity and the
origins of modularity. Res Microbiol 2004; 155: 370 5.
110. Gogarten JP, Townsend JP. Horizontal gene transfer, genome
innovation and evolution. Nat Rev Microbiol 2005; 3: 679 87.
111. Mozwecz H, Pavel D, Pitrak D et al. Erythromycin stearate as prokinetic agent in postvagotomy gastroparesis. Dig Dis Sci 1990; 35: 9025.
112. Quigley EM. Chronic intestinal pseudo-obstruction. Curr Treat
Options Gastroenterol 1999; 2: 239 50.
113. Zaloga GP. Early enteral nutritional support improves outcome:
hypothesis or fact? Crit Care Med 1999; 27: 259 61.
114. Miskovitz P. Gastric prokinetic motility therapy to facilitate early
enteral nutrition in the intensive care unit. Crit Care Med 2002; 30: 13867.
115. Heyland DK, Cook DJ, Guyatt GH. Enteral nutrition in the critically ill patient: a critical review of the evidence. Intensive Care Med
1993; 19: 43542.
116. Ritz MA, Fraser R, Edwards N et al. Delayed gastric emptying
in ventilated critically ill patients: measurement by 13C-octanoic acid
breath test. Crit Care Med 2001; 29: 1744 9.
117. Ritz MA, Fraser R, Tam W et al. Impacts and patterns of
disturbed gastrointestinal function in critically ill patients. Am J
Gastroenterol 2000; 95: 3044 52.
118. Tarling MM, Toner CC, Withington PS et al. A model of gastric
emptying using paracetamol absorption in intensive care patients.
Intensive Care Med 1997; 23: 256 60.
119. Kao CH, ChangLai SP, Chieng PU et al. Gastric emptying in
head-injured patients. Am J Gastroenterol 1998; 93: 1108 12.
120. Mentec H, Dupont H, Bocchetti M et al. Upper digestive intolerance during enteral nutrition in critically ill patients: frequency, risk
factors, and complications. Crit Care Med 2001; 29: 1955 61.
121. Zaloga GP, Marik P. Promotility agents in the intensive care
unit. Crit Care Med 2000; 28: 26579.
122. Doherty WL, Winter B. Prokinetic agents in critical care. Crit
Care 2003; 7: 2068.
123. Yavagal DR, Karnad DR, Oak JL. Metoclopramide for preventing pneumonia in critically ill patients receiving enteral tube feeding: a
randomized controlled trial. Crit Care Med 2000; 28: 1408 11.
124. Kalliafas S, Choban PS, Ziegler D et al. Erythromycin facilitates
postpyloric placement of nasoduodenal feeding tubes in intensive care
unit patients: randomized, double-blinded, placebo-controlled trial.
JPEN J Parenter Enteral Nutr 1996; 20: 385 8.
125. Griffith DP, McNally AT, Battey CH et al. Intravenous erythromycin facilitates bedside placement of postpyloric feeding tubes in critically ill adults: a double-blind, randomized, placebo-controlled study.
Crit Care Med 2003; 31: 39 44.
126. Paz HL, Weinar M, Sherman MS. Motility agents for the placement of weighted and unweighted feeding tubes in critically ill patients.
Intensive Care Med 1996; 22: 301 4.
127. Dive A, Miesse C, Galanti L et al. Effect of erythromycin on
gastric motility in mechanically ventilated critically ill patients: a doubleblind, randomized, placebo-controlled study. Crit Care Med 1995; 23:
135662.
128. Dive A, Garrino M, Nizet H et al. Gastric microbial overgrowth
and retrograde colonization of the ventilated lung: effect of a digestive
prokinetic therapy. In: Seventh European Congress of Intensive Care
Medicine, Innsbruck, Austria, 1994. p. 757.
129. Reignier J, Bensaid S, Perrin-Gachadoat D et al. Erythromycin
and early enteral nutrition in mechanically ventilated patients. Crit Care
Med 2002; 30: 123741.
130. Jooste CA, Mustoe J, Collee G. Metoclopramide improves gastric
motility in critically ill patients. Intensive Care Med 1999; 25: 4648.
131. Calcroft RM, Joynt G, Hung V. Gastric emptying in critically ill
patients: a randomised, blinded, prospective comparison of metoclopramide with placebo. Intensive Care Med 1997; 23 Suppl: S138.

Review
152. Burgess DS. Pharmacodynamic principles of antimicrobial
therapy in the prevention of resistance. Chest 1999; 115: 19S23S.
153. Zanelli G, Pollini S, Sansoni A et al. Molecular typing of
Staphylococcus aureus isolates from an intensive care unit. New
Microbiol 2004; 27: 293 9.
154. Crespo MP, Woodford N, Sinclair A et al. Outbreak of
carbapenem-resistant Pseudomonas aeruginosa producing VIM-8, a
novel metallo-b-lactamase, in a tertiary care center in Cali, Colombia. J
Clin Microbiol 2004; 42: 5094 101.

155. Woodford N, Tierno PM Jr Young K et al. Outbreak of

Klebsiella pneumoniae producing a new carbapenem-hydrolyzing class
A b-lactamase, KPC-3, in a New York Medical Center. Antimicrob
Agents Chemother 2004; 48: 47939.
156. Kreymann KG, Berger MM, Deutz NE et al. ESPEN guidelines on enteral nutrition: intensive care. Clin Nutr 2006; 25:
210 23.
157. Dallantonia M, Wilks M, Coen PG et al. Erythromycin for prokinesis: imprudent prescribing? Crit Care 2005; 10: 112.

Downloaded from http://jac.oxfordjournals.org/ by guest on December 17, 2016

358