International Journal of Antimicrobial Agents 29 (2007) 3–8

Review

The 50th anniversary of the discovery

of 6-aminopenicillanic acid (6-APA)
G.N. Rolinson a , A.M. Geddes b,∗
a Formerly Associate Director of Research (Microbiology), Beecham Pharmaceuticals, Brockham Park, Betchworth, UK
b Emeritus Professor of Infectious Diseases, University of Birmingham, Birmingham, UK

I have pleasure in introducing this review, which is published in celebration of the half century since the discovery of the penicillin
‘nucleus’—6-aminopenicillanic acid (6-APA). This discovery enabled the development of the semi-synthetic penicillins that have proved
so important in clinical practice and that are only under serious threat today with the advent of virulent new clones of methicillin-resistant
Staphylococcus aureus (MRSA).
The authors are a distinguished scientist who was one of the team of chemists and microbiologists at Beecham Research Laboratories
involved in the discovery of 6-APA in 1957, and a clinician who participated in many of the early clinical studies of the semi-synthetic
penicillins and cephalosporins that defined the golden age of antimicrobial chemotherapy.
I.M. Gould
Reviews Editor

Abstract

This year (2007) marks the 50th anniversary of the discovery of 6-aminopenicillanic acid (6-APA), the precursor of all semi-synthetic
penicillins and cephalosporins—the ␤-lactam antibiotics. This review, by a scientist who played a major part in the discovery and a physician
who participated in the early clinical trials of these antibiotics, tells the story of the discovery and of the early development of the ␤-lactam
antibiotics that revolutionised the treatment of infections.
© 2006 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Keywords: ␤-Lactam antibiotics; History of medicine

1. Introduction compounds, penicillin G and penicillin V, but with 6-APA as

The year 2007 marks the 50th anniversary of the discovery
of the so-called penicillin nucleus, 6-aminopenicillanic acid
(6-APA). This discovery made possible the development
of the semi-synthetic penicillins that became one of the
most important groups of antibiotics in clinical practice. In
addition, the discovery of 6-APA provided the incentive for
the development of other types of ␤-lactam antibiotics.
When the discovery of 6-APA was made in 1957, the peni-
cillin family, from a clinical point of view, comprised just two
∗ Corresponding author.
E-mail address: A.M.Geddes@bham.ac.uk (A.M. Geddes).
the starting point for the preparation of new penicillins the
family grew to more than 20 different compounds in clinical
use by the end of the 1970s.
2. Early work on the preparation of new penicillins
Research on the preparation of new penicillins that might
have advantageous properties has quite a long history. In the
early work on penicillin fermentation in the 1940s it was
found that the mould Penicillium chrysogenum produced not
just one penicillin but a small family of penicillins, differing
only in the nature of an acyl side chain attached to a fused
␤-lactam thiazolidine ring system, which has become known

0924-8579/$ – see front matter © 2006 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
doi:10.1016/j.ijantimicag.2006.09.003
4 G.N. Rolinson, A.M. Geddes / International Journal of Antimicrobial Agents 29 (2007) 3–8
as the penicillin nucleus. In the UK, each member of the
penicillin family was designated by numerals and in the USA
by the letters X, G, F and K.
It was then discovered that addition of phenylacetic acid to
the fermentation medium resulted in the preferential forma-
tion of penicillin G, the phenylacetic acid being accepted by
the mould as a precursor for the particular side chain present
in penicillin G, namely a benzyl group. Evaluation of the
individual penicillins X, G, F and K had already shown that
they differed in their microbiological and pharmacological
properties and this stimulated interest in the possibility of
preparing further penicillins with different side chain struc-
tures that might show advantageous properties compared with
penicillin G. Research showed that a great many new peni-
cillins could indeed be produced if the desired side chain
structure was provided in the fermentation medium in the
form of a precursor [1], and one of the penicillins produced
in this way was penicillin V, although the important prop-
erties of acid stability and absorption when administered by
mouth were not appreciated until the work of Brandl and
Margreiter in 1954 [2]. A large number of new penicillins
were produced by fermentation using side chain precursors,
but apart from penicillin V none found any place in clinical
practice.
Another approach to the preparation of new types of peni-
cillin was chemical modification of the naturally occurring
penicillin, penicillin X, the para hydroxy group in the side
chain of the penicillin facilitating such modifications [3]. A
number of semi-synthetic penicillins were prepared in this
way but none was considered to be superior to penicillin G.
3. The discovery of 6-APA
Although the work with penicillin X and side chain
precursors did not lead to any new penicillins of clinical
importance (with the exception of penicillin V), these stud-
ies provided the incentive for a programme of work in which
p-aminobenzyl penicillin was to be used as the starting point
for the preparation of new penicillins, the p-amino group in
the side chain of this penicillin providing the point through
which chemical modification could be carried out [4]. The
p-aminobenzyl penicillin itself was prepared by fermenta-
tion using p-aminophenylacetic acid as the precursor, and
production of this penicillin was followed using two differ-
ent assay procedures. One was the conventional cup-plate
bioassay and the other was a chemical method not depending
on the antibacterial activity of the penicillin. It was found
that when the side chain precursor was present in the fer-
mentation medium the two assay methods gave very similar
results, but in control fermentations in which the precursor
was absent the chemical assay gave a very much higher value
than the bioassay [5]. The interpretation of these results was
that under fermentation conditions in which there was a lack
of available side chain structures, the nucleus of the peni-
cillin molecule was produced without any side chain attached.
Such a compound could be expected to be assayed by the
chemical method and might well show little activity in the
bioassay. This interpretation proved to be correct and the
compound was identified as 6-APA. Experiments showing
this to be the case were carried out in the laboratories of
Beecham Research in the summer of 1957 and these findings
were published by Batchelor et al. in Nature in January 1959
[6].
4. Early reports of possible relevance to the discovery
of 6-APA
The discovery of 6-APA in 1957 prompted a literature
search for any reports that might be relevant, which revealed
a publication by Kato in 1953 in the Journal of Antibiotics
(Tokyo) [7] in which the author reported that penicillin fer-
mentations contained a component that Kato described as
‘imperfect’ penicillin (or ‘incomplete’ penicillin, depending
on the translation). Kato did not isolate this compound or
characterise it in any way and it was certainly not reported to
be 6-APA. No further publications by Kato appeared on this
subject and the nature of the compound in question remains
obscure.
The literature search also revealed a publication by Sak-
aguchi and Murao in 1950 [8] and a later paper by Murao in
1955 [9]. These reports claimed that an enzyme preparation
from P. chrysogenum Q176 could bring about the splitting of
penicillin G to give phenylacetic acid and a compound that
the authors called ‘penicin’. The structure shown for penicin
was indeed the structure of 6-APA. However, the chemical
and physical properties given for penicin do not agree with
those of authentic 6-APA. Moreover, the Beecham Research
Laboratories received a sample of the enzyme from Murao,
through the good offices of Sir Ernest Chain, together with a
culture of the strain of P. chrysogenum used by Murao. Thor-
ough testing of the enzyme and the culture of P. chrysogenum
failed to detect the formation of any 6-APA by deacylation of
penicillin G. Moreover, no published confirmation of the Sak-
aguchi and Murao work has appeared in any of the scientific
literature. The identity of the compound ‘penicin’ therefore
remains unclear.
5. Production of 6-APA by enzymatic hydrolysis of
penicillin
Notwithstanding the inability to confirm the work of Sak-
aguchi and Murao, a programme of work was begun in the
Beecham Research Laboratories at the end of 1957 in which
microorganisms were screened for possible production of a
penicillin deacylase.
It was found that a deacylase was indeed produced by a
number of actinomycetes as well as certain filamentous fungi,
although not by P. chrysogenum. Moreover, with this deacy-
lase, penicillin G was split only very slowly, but penicillin V
 G.N. Rolinson, A.M. Geddes / International Journal of Antimicrobial Agents 29 (2007) 3–8
was deacylated very readily [10]. A process for 6-APA pro-
duction was developed using a deacylase from Streptomyces
lavendulae and penicillin V as the substrate, and a patent for
this process was filed by Beecham Pharmaceuticals in March
1959.
Subsequently, a deacylase of bacterial origin was discov-
ered independently in a number of laboratories [10–13] and
using this enzyme penicillin G was deacylated very readily.
Later, a process for chemical deacylation of penicillin was
developed.
6. Semi-synthetic penicillins
With the availability of 6-APA, the way was open for the
preparation of a wide range of new penicillins, but it should
be remembered that there was no guarantee that any of the
penicillins prepared in this way would have advantageous
properties compared with penicillin G or V. The work with
side chain precursors in fermentation and the chemical modi-
fication of penicillin X had not led to any penicillin of clinical
importance other than penicillin V. Nevertheless, the objec-
tives clearly presented themselves. One was the possibility
of preparing a penicillin active against the penicillin-
resistant staphylococci that had become a serious clinical
problem.
Writing in the British Medical Journal in 1956 [14], just 1
year before the discovery of 6-APA, the late Paul Garrod said
‘The most disquieting feature of present-day hospital prac-
tice is the prevalence of antibiotic resistant staphylococcal
infections’. The basis of penicillin resistance in Staphylococ-
cus aureus had already been shown by Kirby in 1944 [15]
to be production of ␤-lactamase, referred to at that time as
penicillinase, and with 6-APA as the starting point this clearly
offered the possibility of preparing penicillins that were stable
to attack by this enzyme.
The first semi-synthetic penicillin stable to staphylococcal
penicillinase and clinically effective against penicillin-
resistant S. aureus was methicillin [16]. This was followed
by penicillins that were more active than methicillin and
that were also well absorbed when given by mouth, notably
cloxacillin and flucloxacillin.
Methicillin was introduced in 1960, just 3 years after the
discovery of 6-APA, and in the following year (1961) ampi-
cillin made its appearance. Further research in 1964 showed
that the introduction of a p-hydroxy group in the side chain
of ampicillin led to greatly improved absorption following
oral administration and this penicillin, namely amoxicillin,
became the most widely prescribed antibiotic in clinical prac-
tice.
In 1967, carbenicillin was introduced, the first penicillin,
indeed the first ␤-lactam antibiotic, clinically active against
Pseudomonas aeruginosa. At that time, the range of antibi-
otics available for the treatment of Pseudomonas infections
was extremely limited; gentamicin had only recently been
introduced and the carbapenems and cephalosporins active
5
against P. aeruginosa had yet to make their appearance.
In 1970, an analogue of carbenicillin appeared, namely
ticarcillin, and in the mid 1970s the ureidopenicillins were
introduced, including azlocillin and piperacillin.
As the development of the semi-synthetic penicillins pro-
gressed, the role of ␤-lactamase as a resistance mechanism
steadily increased in importance. As a result, synthesis of
penicillins stable to ␤-lactamases had even greater signifi-
cance and in 1981 temocillin was introduced. This penicillin
showed a very high degree of stability against a number of
␤-lactamases, including the extended-spectrum ␤-lactamases
[17], and, interestingly, temocillin has recently re-entered the
market.
7. ␤-Lactamase inhibitors
An alternative approach to the problem of ␤-lactamase-
mediated resistance to penicillin has been the use of a
␤-lactamase inhibitor. In 1967, a programme of work was
begun in the Beecham Research Laboratories in which
microorganisms were examined for the possible production
of a naturally occurring inhibitor of ␤-lactamase [18]. This
resulted in the discovery of an inhibitor produced by a strain
of Streptomyces olivaceus. Further work led to the discovery
of clavulanic acid, produced by Streptomyces clavuligerus,
and in 1980 a combination of amoxicillin with clavulanic
acid was introduced, namely co-amoxiclav.
8. The influence of 6-APA on development of the
cephalosporins
Shortly after the introduction of the first semi-synthetic
penicillins, the first cephalosporins made their appearance
in clinical practice, with cefalothin in 1962 and cefalori-
dine in 1964. As with the semi-synthetic penicillins, the
semi-synthetic cephalosporins are derived from a nucleus,
the nucleus in this case being that of the naturally occur-
ring cephalosporin, cephalosporin C. However, unlike the
penicillin nucleus 6-APA, the cephalosporin nucleus 7-
aminocephalosporinic acid (7-ACA) is not itself a naturally
occurring compound; it can only be obtained by deliberate
removal of the side chain from cephalosporin C. A chemical
process was devised to enable this to be done, but the ques-
tion arises as to whether there would have been the incentive
to do this had it not been for the discovery of 6-APA and the
demonstration that important new penicillins could be pre-
pared from this nucleus. With hindsight, of course, it could be
said that it was obvious that removal of the side chain from
cephalosporin C would provide a nucleus from which new
cephalosporins could be prepared, but in that case we have to
ask why it was not obvious to do this in the penicillin field.
The fact is that prior to the discovery of 6-APA no attempt
had been made to remove the side chain from penicillin and
such a step never even appears to have been considered. Had
6 G.N. Rolinson, A.M. Geddes / International Journal of Antimicrobial Agents 29 (2007) 3–8
it not been for the discovery of 6-APA, therefore, the deacy-
lation of cephalosporin C might not have been attempted, in
which case there would not have been the development of the
cephalosporins.
9. Translation of the discovery of 6-APA into clinical
practice
9.1. The penicillins
In the early 1960s there were only around six antimicrobial
agents available for the treatment of infections—penicillin,
chloramphenicol, the tetracyclines, erythromycin, strepto-
mycin and the sulphonamides. Rapidly emerging microbial
resistance and the discovery that certain of these agents
had unacceptable side effects, e.g. chloramphenicol caused
aplastic anaemia and the tetracyclines stained developing
teeth, were the catalysts for the search for new anti-infective
drugs.
While working initially in Edinburgh in the 1960s, and
later in Birmingham, one of the authors (A.M.G.) was
involved in clinical trials of a number of the new semi-
synthetic ␤-lactam antibiotics. The first new ␤-lactam agent
to be studied was ampicillin, which proved to be enormously
successful in the management of a wide range of infections,
particularly those affecting the respiratory and renal tracts.
A study was made [19] of the efficacy of ampicillin in the
treatment of enteric fever, in which it proved to be as effi-
cacious as chloramphenicol, one of the earliest comparative
clinical trials that later became mandatory for the registra-
tion of new antimicrobial agents. This study was recorded in
a monograph, published by the Fellowship of Postgraduate
Medicine, which reported the proceedings of the First Inter-
national Conference on Therapy with the New Penicillins,
held in London in 1964.
Methicillin [20] was another new semi-synthetic ␤-
lactam antibiotic introduced in the 1960s. Its activity against
penicillinase-producing S. aureus was especially welcome at
a time when penicillin-resistant staphylococci had become a
major problem in hospitals.
Methicillin was superseded by cloxacillin (except for lab-
oratory sensitivity testing of staphylococci), which was also
stable to ␤-lactamases and was more active than methicillin
and could be administered both by injection and by mouth
[21]. Cloxacillin (1962) was not particularly well absorbed
from the gastrointestinal tract and was replaced in 1970 by
its better absorbed analogue, flucloxacillin [22].
As ampicillin is also not particularly well absorbed from
the gut, workers at the Beecham Research Laboratories syn-
thesised amoxicillin (␣-amino-p-hydroxybenzyl penicillin).
Studies [23] confirmed that amoxicillin was better absorbed
following oral administration, resulting in higher blood levels
than those achieved following equivalent doses of ampi-
cillin. The antibiotic proved to be valuable in the treatment
of infections of the urinary and biliary tracts as well as for
exacerbations of chronic bronchitis caused by Streptococcus
pneumoniae and Haemophilus influenzae.
The discovery of carbenicillin [24] followed by ticarcillin
[25], then piperacillin [26] and mezlocillin and azlocillin
[27], all with activity against P. aeruginosa, proved valu-
able for the treatment of infections in immunocompromised
patients in whom this organism is an important pathogen.
Inactivation of amoxicillin by ␤-lactamases was a major
problem as amoxicillin-resistant bacteria became increas-
ingly common in the 1970s. Clavulanic acid is an inhibitor
of ␤-lactamases and, when combined with amoxicillin as
co-amoxiclav, has a wide spectrum of activity that includes
penicillin-resistant staphylococci and Bacteroides fragilis.
The combination proved to be very effective for the treatment
of a wide range of infections [28].
9.2. The cephalosporins
One of the first cephalosporin antibiotics was cefaloridine
[29]. This was an exciting broad-spectrum antibiotic effec-
tive in a wide range of infections, including pneumococcal
meningitis. Unfortunately it proved to be nephrotoxic and
was eventually withdrawn.
Fortunately, other cephalosporins with broad antibacte-
rial spectra became available, including cefuroxime [30],
ceftazidime [31] and cefotaxime [32].
9.3. The cephamycins
Cefoxitin, a semi-synthetic cephamycin antibiotic, was
introduced in the early 1970s and proved to be particu-
larly effective for the treatment of intra-abdominal sepsis
[33].
9.4. The thienamycins
A further development in the ␤-lactam group of antibi-
otics was the introduction of the first carbapenem antibiotic,
imipenem, a combination of N-formimidoyl thienamycin and
cilastatin. Cilastatin was necessary to protect the kidneys
from tubular damage caused by thienamycin. This antibiotic
has a particularly broad antibacterial spectrum and has been
used to treat a wide variety of infections [34].
10. Discussion
The discovery of 6-APA by scientists in the Beecham
Research Laboratories was a major event in the fight against
infection at a time when there was a real danger of the bat-
tle being lost owing to the emergence of bacteria resistant to
available antibiotics and the recognition that certain of the
available agents had potentially serious adverse reactions.
The introduction of immunosuppressive drugs, as well as of
organ transplantation and other major surgical procedures,
and hospital-acquired infections in general resulted in the
 G.N. Rolinson, A.M. Geddes / International Journal of Antimicrobial Agents 29 (2007) 3–8
emergence of ‘difficult to treat infections’, often caused by
resistant bacteria, requiring the availability of new antimicro-
bial agents.
The discovery of 6-APA was followed by major advances
in the development of the ␤-lactam antibiotics, with the sav-
ing of probably millions of lives and a massive reduction in
morbidity from infection.
The ␤-lactam antibiotics as a group are active against the
majority of bacteria causing infections in all systems of the
body and are used therapeutically and prophylactically in
medical, dental and veterinary practice.
All of the original semi-synthetic ␤-lactam agents have
stood the test of time, with the exception of cefaloridine
and methicillin. The 6-APA derivatives have proved to be
remarkably safe drugs that can be administered by mouth
or injection to patients of all ages, even in the presence
of renal and hepatic failure, unlike certain other groups
of antimicrobial agents such as the aminoglycosides and
fluoroquinolones.
The initial clinical trials of the original ␤-lactam antibi-
otics in the 1960s were generally non-comparative studies of
relatively small numbers of patients suffering from a vari-
ety of infections. As a consequence, the time from discovery
of the chemical molecule to the marketplace was relatively
short.
The Safety of Drugs Committee, the first drug regulatory
body in Britain, was established in 1964 and was replaced
by the Committee for the Safety of Medicines (CSM). In the
1960s the Food and Drugs Agency (FDA) was established in
the USA and similar bodies were set up in other countries.
Increasingly stringent regulations dealing with the efficacy
and safety of drugs were put in place, and the time between
the discovery of a potential antibiotic and its availability for
clinical use increased significantly. Clinical trials today are
complex and demanding as well as expensive, and are one
reason for the decrease in the availability of new antimicrobial
agents.
The past 50 years have been an exciting period in the
annals of infectious diseases. The discovery of 6-APA opened
the way for the development of the largest group of antibi-
otics yet introduced into clinical practice. We pay tribute to
the many scientists and clinicians who made possible the
discovery and development of the semi-synthetic ␤-lactam
antibiotics.
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