Journal of Antimicrobial Chemotherapy (2009) 63, Suppl.

1, i18 i20
doi:10.1093/jac/dkp077

Why monotherapy?
Keith J. Williams*
KW Drug Developments Ltd, Nightingale House, 5 Maplewood Road, Wilmslow, Cheshire SK9 2RY, UK
This is an account of the history of the early days of monotherapy of infections in neutropenic patients
with haematological malignancies. A chance encounter with Ben de Pauw led to his introduction to clinical drug development research, introduced him to Peter Donnelly who was studying ceftazidime at the
Hammersmith Hospital in London and led to a series of collaborative studies at the start of a distinguished research career. This paper is dedicated to Ben de Pauw and also to the memory of my mentor,
Roy Foord, who had the vision to go against his initial cautious instinct and allow me to convince him of
the merits of these studies when combinations including aminoglycosides were standard. These initial
studies also contributed to the concept of initial empirical monotherapy with re-appraisal at 4872 h.
Keywords: ceftazidime, meropenem, neutropenia

Chemotherapy regimens provided a means to control haematological malignancies but led to periods of neutropenia, during
which patients were prone to systemic infections from multiple
sources and a wide range of bacteria requiring empirical combination therapy with aminoglycosides, and the safer b-lactam
antibiotics. These combinations offered synergistic activity by
combining different modes of action according to Jean
Klastersky and the EORTC.1 Monotherapy was not an option in
1980 as no single agent had sufficiently broad activity and
aminoglycosides had to be included to cover problematic
bacteria such as Pseudomonas aeruginosa.
It was at this time that I was interviewed by Dr Roy Foord, the
Medical Director at Glaxo Group Research in Greenford, near
London, the site where William Perkin had established a dyestuffs
industry that was a forerunner of the pharmaceutical industry.
I recall Dr Foord telling me that although I knew nothing
about antibiotics, I spoke enthusiastically and clearly communicated my own research and he offered a chance of a clinical
research position. My early experience was on late-stage studies
and reports of cefuroxime, but there was excitement within the
company about a novel broad-spectrum cephalosporin that was
to become ceftazidime, or as we affectionately called it CAZ,
which offered a significant enhancement of activity against
P. aeruginosa and other Gram-negative bacilli. Gaps in my
knowledge of microbiology were filled by Paul Harper, Peter
Acred, Cynthia OCallaghan and later, Anne Harris.
At an early stage, I had the distinction of having received
more ceftazidime than any person on the planet; three intravenous courses, each of 10 days, giving multiple blood and urine
samples and being lanced to measure my prothrombin time.

Ceftazidime had an initial scare when 3 of the first 11

patients treated suffered mild rash, but clinical trials were soon
underway, and my role was to establish clinical studies in
Austria, the UK and then Germany and the Netherlands. Initial
studies were on urinary infections and pneumonia and on a
serious infection protocol as the dose was gradually raised
from 500 mg three times daily to 2000 mg three times daily and
experience extended to cystic fibrosis and even Pseudomonas
meningitis.
At the Radboud hospital in Nijmegen, I established a study
on ICU patients with Dr Roelof Van Dalen, in which we
explored the pharmacokinetics in dialysis patients. On a routine
visit to his clinic towards the end of 1981, I was checking his
supplies and realized some vials were unaccounted for. These
were the formative years of good clinical practice and upon
questioning, he admitted that another doctor along the corridor
had stolen some of his supply. I set out to investigate and that
was my first encounter with Dr Ben E. de Pauw. After I had reprimanded him, he shrugged his shoulders, arguing that he had
taken ceftazidime to rescue patients who had failed on the usual
EORTC regimens and he showed me that he had also stolen
some of our stupid case record forms (CRFs), presenting me
with the most perfectly completed CRFs that I had ever seen.
I returned to London and explained to Roy Foord that I had
discovered a new potential investigator, who although he had
never really done clinical trials before, had documented his
cases so well. The patients treated had received a combination of
an aminoglycoside and cephalosporin, and were failing to
respond, usually due to the isolation of Pseudomonas.
Ceftazidime was added in place of cefotaxime. I recall that Roy
was initially against a study, pointing out the lack of evidence
for monotherapy, and yet I convinced him that the combination

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*Tel: 44-772-555-6604; Fax: 44-1625-535010; E-mail: kjwilliams510@aol.com

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Introduction

Why monotherapy?
cephalothin, gentamicin and carbenicillin versus ceftazidime as
empirical therapy, Warrens group from Cambridge and Bodey
from Houston.
The clinical development of ceftazidime had taken just
3 years and there was much excitement with the launch at the
International Congress of Chemotherapy (ICC) meeting in
Vienna later in 1983. Many of the investigators gathered and
shared their experiences.
In order to evaluate the benefits of enhancing initial empirical Gram-positive cover, ceftazidime was compared with gentamicin combined first with flucloxacillin4 and then cephalothin.5
A further approach to this problem was taken with teicoplanin.6
The latter study was presented at the ICC meeting in Kyoto in
1985 and it was while standing by a poster of the results that
Richard Bax began to entice me to join what was then ICI
Pharmaceuticals to repeat this work with a new drug that was to
become meropenem.
One of the minor irritations of ceftazidime was that it was
formulated in such a way that reconstitution of the drug led to a
release of carbon dioxide and the vials had to be vented to allow
its release or otherwise it would fizz out of control. Nurses
occasionally complained of being showered with the drug,
which had the odour of cat urine. Ben was one of the few who
published a study in neutropenics of a new arginine salt that circumvented this issue though the original remained a success and
the arginine salt was never released.7
Within the growing body of evidence with ceftazidime
monotherapy, it became possible to examine subsections of the
data and we reported on the treatment of pneumonia in immunocompromised patients,8,9 on 27 Pseudomonas infections
treated between 1981 and 1984 and further extended in 1986,10
and showed that ceftazidime did not enhance cyclosporine
nephrotoxicity in bone marrow transplant patients.11 One of
the subinvestigators in Nijmegen at the time was Dr Stans
Verhagen, who compiled a thesis based on his experience in
the studies.
de Pauw continued to study ceftazidime further in wider
collaborative studies.12,13 It was inevitable that I would return
to Nijmegen by the time that meropenem was ready to be
tested in neutropenic patients. Initially, we only planned a
study of 200 patients with a parallel study planned in the USA.
However, the Meropenem Study Group, which also included
centres in Leuven and London, recruited their 200 patients
before the USA study even started and so it was extended. The
data were first presented at the Immunocompromised Host
meeting in Colorado and subsequently published.14 de Pauw
and co-workers15 also performed further collaborative studies
with meropenem.
Of course many other antimicrobials have followed the
monotherapy path and the EORTC and others have published
many studies, not only on ceftazidime and meropenem,16 but
I hope my insight into the early studies at Glaxo and the significant role of Ben de Pauw are appropriate in the context of honouring his contributions in this area.
The role of monotherapy has been reviewed in the
literature.17

Transparency declarations
None to declare.

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had failed and that ceftazidime replacing only one of the drugs
was effectively acting alone. We reached a middle ground in
which I drafted a protocol and de Pauw was allowed a pilot
study of 30 cases using ceftazidime in combination with amikacin in patients who were still febrile after 48 72 h of standard
therapy.
On 3 February 1982, I summarized our experience with ceftazidime in neutropenics in a letter to Jim Chubb, whose team
was setting up studies of ceftazidime in the USA in the newly
established Research Triangle Park offices in North Carolina.
This included the statement: de Pauw has used additional antibiotics in most cases so far but is now sufficiently impressed
with ceftazidime to proceed with a trial of monotherapy. A
couple of his CRFs were included as evidence.
By this time in the UK we were broadening our experience,
and other early investigators included a group led by Zamiri in
Cardiff whose early experience was not so good, a serious infection study with Gozzard and Geddes in Birmingham that
included some neutropenic patients and that led to a study that
I had just established with Dr Mike Leylands group in
Birmingham, where I collaborated closely with Virginia Clough,
and a study coordinated by Carolyn Davey-Smith with Duerden
and Lilleyman in leukaemic children in Sheffield that had
entered nine patients in a comparison with tobramycin plus azlocillin, though most did not have bacteria isolated. Two other
studies about to start were with Rod Warren at Addenbrookes
in Cambridge and with Bellingham in Liverpool (only 1 g 8
hourly). Early results in the USA had until then been less
favourable. Nevertheless, it was this early evidence that convinced the US team to establish a landmark study with Pizzo
et al. 2 at NIH and to introduce other US studies with Bodey,
Ramphal and Schimpf, and also with Feld in Canada.
Later in 1982, I established a study with Catovsky at the
Hammersmith Hospital in London, working closely with their
microbiologist Peter Donnelly, who through this experience met
Ben de Pauw and eventually joined him in Nijmegen. In April
1982, I collated the overall experience for a letter that Roy
Foord sent to Jean Klastersky setting out the updated experience
and trying to persuade the EORTC to take up a monotherapy
study. At the time, the EORTC were studying amikacin in combination with ticarcillin, azlocillin or cefotaxime.
Meanwhile in Nijmegen, I was joined by my colleague Theo
Bothof in monitoring the progress of the first major randomized
trial of ceftazidime monotherapy in which de Pauw et al. 3 compared ceftazidime with a combination of gentamicin and cefotaxime. We learnt a lot from those early studies, including the
fact that the usual microbiological assessments of success and
failure were not discriminatory and we introduced terms such as
success with modification and also gained the experience
that on average an afebrile response could not be expected by
48 72 h, but with confidence gained, monotherapy could be
continued. It was important to have clear criteria for adding
further antibiotics and to record which they were and why they
were given.
This study, along with other experiences of monotherapy,
was presented in the final session of the ceftazidime (Fortum)
launch meeting at the Barbican in London in 1983 and subsequently published. The session was chaired by Klastersky with
the opening words the most demanding trial of an antimicrobial
that you can imagine is to give it to a granulocytopenic patient.
Other reports were by Reuben Ramphal, Phil Pizzo on

Williams
References

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