Journal of Antimicrobial Chemotherapy (1995) 36, Suppl.

A, 135-143

Clinical evaluation of meropenem versus ceftazidime for the treatment of

Pseudomonas spp. infections in cystic fibrosis patients

S. Byrne', J. Maddison*, P. Connor', I. Doughty*, M. Dodd', M. Jenney*,

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A. K. Webb** and T. J. David'

'Department of Health, University of Manchester, hMonsall Hospital, and

department of Microbiology, Booth Hall Children's Hospital, Manchester, UK

Cystic fibrosis patients (children and young adults) with Pseudomonas spp. chest
infections were treated with meropenem or ceftazidime. This study was the first to
investigate the use of meropenem in cystic fibrosis. Meropenem was well tolerated with
only transient elevations of serum transaminases. No patient experienced nausea and
vomiting, even when meropenem was administered as a bolus injection. This allowed
home therapy to be used. Meropenem appeared to be at least as active as ceftazidime
even at the low doses used. Patients showed a greater improvement in respiratory
function on meropenem than ceftazidime. Only one patient (out of 60 courses) failed
to respond to meropenem (98% success rate) compared with two failures out of 21
episodes with ceftazidime (90% success rate). There was little emergence of resistance
to meropenem even though some patients were treated up to eight times over a 2 year
period.

Introduction
Cystic fibrosis is the commonest lethal inherited disease in Europe and the USA with most
patients being diagnosed in early childhood (Koch & Heiby, 1993). Regular use of
effective antibiotics together with better management of the underlying defect has led to
a significant increase in the long-term survival of patients, and an improved quality of
life (David, 1990).
However, chronic pulmonary sepsis in cystic fibrosis poses one of the most difficult
challenges for an antibacterial agent. The principal organisms associated with morbidity
and mortality due to lung damage are those of the genus Pseudomonas, especially
Pseudomonas aeruginosa. An antibacterial agent should therefore be effective against the
various phenotypes of this organism while retaining activity against Haemophilus
influenzae and Staphylococcus aureus. Activity against Burkholderia (Pseudomonas)
cepacia is also desirable. There is good evidence of person to person transmission of
B. cepacia in cystic fibrosis clinics and summer camps, and its isolation is often associated
with a marked clinical deterioration (LiPuma et al., 1990). This organism has caused
significant problems in our clinics; it has been reported that meropenem, a new
carbapenem antibiotic, may show enhanced activity against B. cepacia (Iaconis et al.,

'Correspondence to: A. K. Webb, Adult Cystic Fibrosis Unit. Northwest Lung Cenire. Wythenshawe
Hospital, Southmoor Road, Wythenshawe. Manchester M23 9LT, UK.

135
0305-7453 95 36AI35 + 09 S08.00 0 o 1995 The British Society for Antimicrobial Chemotherapy
136 S. Byrne et al.

1993). We have also identified Stenotrophomonas (Xanthomonas) maltophilia in patients

(Gladman et al., 1992) and further clinical problems have been reported with
Pseudomonas stutzeri and the 'RVT strain of Pseudomonas from the Royal Victoria
Infirmary, Newcastle, UK.
The phenotype of/5, aeruginosa expressed in the lungs of patients with cystic fibrosis
is quite distinct from that expressed in normal human tissue. Furthermore, the patient
is normally colonised by bacteria of different morphologies (smooth, rough, mucoid),
with different sensitivities and, possibly, other Pseudomonas species (Govan, Doherty &
Glass, 1987). Following colonisation, it is rare to eradicate Pseudomonas spp., except
transiently. The aim of antibiotic therapy is to improve lung function and clinical well

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being by decreasing the bacterial load, a direct effect of antibiotic action. In addition,
antibiotic therapy inhibits the production by bacteria of enzymes, such as proteases and
cathepsins, that cause further lung damage. However, in cystic fibrosis, high doses of
antibacterials are required to combat the high bacterial load and overcome the difficulty
of penetrating the mucus layers surrounding the microcolonies of Pseudomonas spp. in
the lung; high doses are also required to penetrate poorly perfused pus-filled cavities and
to overcome the enhanced renal clearance of antibacterials that occurs in cystic fibrosis.
The regular antibacterial treatment required by cystic fibrosis patients may lead to the
selection of resistant sub-populations of bacteria. This may be avoided by alternating
the administration of agents with different modes of action such as aminoglycosides,
/?-lactams and quinolones. Alternatively, combination therapy can be used but it is
inconvenient and may be associated with an increased incidence of side effects, especially
when aminoglycosides are involved (Pedersen et al., 1987a). Aminoglycosides can be
associated with nephro- and ototoxicity and require careful monitoring of blood levels.
In addition, they penetrate poorly into the mucus layers surrounding the bacterial
microcolonies in cystic fibrosis patients (Gordon, Hodges & Marriott, 1988; Ramphal
et al., 1988). There are also concerns about using quinolones in children because of
the adverse effects seen on growing cartilage in animals, and they have been associated
with rapid emergence of resistance (Bosso, 1992). Ceftazidime has proven to be a
well-tolerated, effective treatment, but it has only limited activity against staphylococci,
some resistance is found in P. aeruginosa, and allergic reactions have been reported
(Fiel, 1993).
Carbapenems have an ultra-broad spectrum of activity and provide an alternative
choice for treatment. The first available carbapenem, imipenem, must be given in
combination with a renal dehydropeptidase inhibitor, cilastatin, in order to prevent renal
breakdown of the active imipenem. In a study involving ten cystic fibrosis patients, the
imipenem/cilastatin combination given at a dosage of 45 mg/kg/day selected resistant
strains of P. aeruginosa in all patients treated (Pedersen el al., 1985). Another study in
the same centre showed that seven of ten patients receiving imipenem/cilastatin at a
dosage of 100 mg/kg/day experienced nausea and vomiting (Pedersen et al., 19876).
In studies involving 2000 strains of P. aeruginosa, including some strains which were
resistant to imipenem, meropenem was shown to be more active in vitro than other
established anti-pseudomonal agents, such as ceftazidime and gentamicin (Turner et al.,
1993).
In previous pharmacokinetic studies, a 1 g infusion of meropenem administered over
30 min reached peak plasma concentrations after 30 min (Bax et al., 1989; data on
file at Zeneca). Peak concentrations in bronchial secretions were achieved 3 h after
infusion, at concentrations that were 20% of serum concentrations (Bergogne-Berezin
 Meropenem in cystic fibrosLs 137

el al., 1994). Following rapid infusion of a 1 g dose of meropenem over 6 min, peak
concentrations in lung and pleural tissue were achieved after 1 h, and those in bronchial
secretions and mucosa after 2 h (Thys, 1992). A 500 mg dose of meropenem has also been
shown to penetrate well into lung tissue and sputum, reaching peak concentrations
0-5—1 -5 h post-dose (data on file at Zeneca).

Methods
The protocol for this study was approved by the Salford Health Authority Research
Ethics Committee and the North Manchester Health Authority Ethics Committee.

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All patients or their parents gave informed consent to enter the study.
In order to be eligible for entry to the study, patients had to have at least one organism
sensitive to treatment, with P. aeruginosa as the predominant pathogen. Patients had
to be aged 2 years or over and not hypersensitive to any /Mactam antibiotic. No
concurrent antibacterials were allowed during the study but other medications were given
as normal.
Sputum samples were collected regularly, both during and between treatment courses,
bacterial strains identified, and semi-quantitative colony counts performed. Pseudo-
monas strains were characterised as smooth, smooth-rough, rough or mucoid. Strains
were maintained and sent to Zeneca Pharmaceuticals where MICs were performed.
All organisms were identified using API strips (API 20 Staph for S. aureus and APIZONE
(Bio Merieux S.A., France) for P. aeruginosa). MICs were determined using Sensititre
plates (Sensititre Ltd, UK). Susceptibility to meropenem, ceftazidime and imipenem was
assessed.
The severity of underlying disease was assessed by the Schwachman score in the
majority of adult patients. Patients were treated every three months and assessed
by measurement of the forced expiratory volume in 1 s (FEV|), forced vital capacity
(FVC), volume of sputum production and bacterial load. A satisfactory response
was defined by improvement of lung function, ease of breathlessness, weight
gain and general well being in comparison with previous known responses in the same
patient.
As bacteriological eradication is not a realistic goal when treating cystic fibrosis
patients, all pre-treatment isolates were examined by a semi-quantitative microbiological
technique to assess whether bacterial load was decreased at the end of therapy.
Patients were treated in a comparative trial with a 2:1 randomisation in favour
of meropenem. Meropenem was given iv at a dosage of 125 mg to I -25 g 8-hourly
depending on the weight of the patient. This dosage was equivalent to half of the
ceftazidime dose (ranging from 250 mg to 2-5 g 8-hourly). Patients within a defined weight
range received a standard dosage of meropenem, approximately equivalent to 25 mg/kg
three times a day, with a maximum dosage in adults of 3-75 g/day. The corresponding
dosage for ceftazidime was 50 mg/kg. At the time of the study, this was the highest dosage
of meropenem given in a clinical trial. First doses of both drugs were administered in
hospital, but many patients continued on therapy at home, allowing them improved
quality of life. Antibiotics were given by short infusion or bolus injection through a
peripheral indwelling intravenous catheter. The mean duration of treatment was 15 days
in both treatment groups.
If patients responded they could be re-entered into the study on the same treatment
as the initial course, as it was considered unethical to deny them a treatment from which
138 S. Byrne et al.

Table I. Characteristics of patients at entry into trial

Characteristic Meropenem Ceftazidime

By patient n = 21 n= 13
Sex
Male 17(63%) 8 (62%)
Female 10(37%) 5 (38%)
Age (years)
Mean (range) 15(4-28) 16(6-33)
Age groups (years)
12 and under 11 (41%) 3 (23%)

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13-17 5(19%) 5 (38%)
18 and over 11 (41%) 5 (38%)
Weight (mean in kg)
Male 41-6 53-4
Female 38-1 36-9
Schwachman score (adults only)
Mean (range) 63(57-71) 69(62-75)
Patient's condition, by episode rr = 60 « = 2I
Good 9(15%) 7 (33%)
Fair 42(70%) 13(62%)
Poor 8(13%) 1 (5%)
Critical 1 (2%) 0

they had benefited. Patients were then monitored in second and subsequent courses to
ensure they continued to respond and that resistant bacteria were not isolated.

Results
Forty patients (representing 81 episodes of Pseudomonas spp. infection), aged 4-33 years,
were treated in the trial. The 2:1 randomisation process gave 27 and 13 evaluable
meropenem and ceftazidime patients, respectively. Sixteen (59%) of the patients
randomised to meropenem and eight (62%) of those randomised to ceftazidime were
under 18 years of age (Table I). Patients were similar demographically but with a higher
proportion of patients under 12 years in the meropenem group. Schwachman scores in

Table II. Number of courses of treatment received

Meropenem Ceftazidime

Patients 27 13
Total episodes treated 60 21
Number of courses of treatment received
(related to the number of episodes)
1 course 27 (44%) 13(62%)
2 courses 18(30%) 5 (24%)
3 courses 12(20%) 3 (14%)
4 courses 3 (7%) 0
Evaluable episodes 54 21
Mean duration of treatment 15 15
(days)
 Meropenem in cystic fibrosis 139

Table III. Clinical response to therapy

Clinical response (%)

Meropenem Ceftazidime

End of therapy (n = 54) (n = 21)

Improvement 98 90
Unchanged/Worse 2 10

Follow-up (4-6 weeks) (n = 50) (n = 20)

Improvement 86 85
Unchanged/Worse 2 5

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Relapse 12 10

adults were comparable between the two groups, with a mean score of 63 in the
meropenem group (n = 11) and 69 in the ceftazidime group (n = 5).
In total, 60 episodes were treated with meropenem and 21 with ceftazidime (Table II).
Six meropenem patients were excluded from the efficacy analysis because of missed doses
and other protocol deviations but all six responded to treatment.
Meropenem was highly effective with a satisfactory clinical response rate of 98% for
all 54 evaluable episodes at the end of therapy. The corresponding result for the 21
evaluable episodes treated with ceftazidime was 90% (Table III). Patients who failed to
respond (i.e. required further immediate intravenous antibacterial agents) were not
eligible for further treatment courses (1 meropenem, 2 ceftazidime). One meropenem
patient with B. cepacia infection failed to respond to treatment and subsequently
died despite 10 days treatment with ceftazidime. Two patients failed to respond to
ceftazidime, one of whom then received meropenem and responded clinically. The second
treatment in these two cases was not included in the summary of efficacy. At follow-up,

40 - Meropenem Ceftazidime

3-5

30

13%
J,5 A f increase
31%
| 2-0 increase

1-5'

10-

0-5
Pre-therapy Post-therapy Pre-therapy Post-therapy
n = 18 n = 16 n=9 n=9
Figure 1. Spirometry results (FEVi) obtained after treatment with meropenem and ceftazidime.
140 S. Byrne et al.

6 Meropenem Ceftazidime

5
1r

4
1
?~16%"~ '"*
i i > -^ increase
3 * 31%
i
A increase
v -*

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2
1_

n
Pre-therapy Post-therapy Pre-therapy Post-therapy
n = 18 rc = 16 n=9 n=9
Figure 2. Spirometry results (FVC) obtained after treatment with meropenem and ceftazidime

4-6 weeks later, 86% of episodes in the meropenem group and 85% in the ceftazidin t
group still showed clinical improvement.
In the adult patients who had spirometry performed, FEV, improved by 3 1 % after
meropenem (n = 16) and 13% after ceftazidime (n = 9) (Figure 1), while FVC improved
by 31 % on meropenem (n = 16) and 16% (n = 9) on ceftazidime (Figure 2). There were
clinically significant decreases in sputum production from 20-8 to 8-7 mL (n = 13) in the
meropenem group and from 20-5 to 7-8 mL (n = 6) in the ceftazidime group.
In all but three episodes, bacterial counts were performed pre-and post-treatment.
Total bacterial counts were reduced in 73% (n = 59) of episodes in the meropenem group
and in 65% (n = 20) in the ceftazidime group. Both meropenem (120 initial bacterial
isolates) and ceftazidime (50 isolates) were found to produce an overall reduction of
colony counts in 60% of all clinical isolates at the end of therapy (Table IV).

Table IV. Response of causative organism at end of therapy

Reduction in colony counts after

Meropenem Ceftazidime
No (%) No (%)

S. aureus 12/18(67%) 5/6 (83%)

P. aeruginosa (smooth) 18/30(60%) 5/10(50%)
P. aeruginosa (smooth-rough) 15/30(50%) 6/12(50%)
P. aeruginosa (mucoid) 25/36 (69%) 12/17(71%)
B. cepacia 1/4(25%) 0/1
S. maltophilia 0/1 0/2
H. influenzae 1/1 (100%) —
Gram-negative bacilli — 2/2(100%)
All clinical isolates 72/120(60%) 30/50(60%)
 Meropenem in cystic fibrosis 141

In addition, bacterial cultures for each patient were followed for the full duration of
the study. Bacterial strains were collected before, during and post-treatment, and for three
months follow-up. Thus patients treated repeatedly were followed for up to one year.
Measurements of MICs were performed for a total of 1516 bacterial isolates. Of these
isolates, 79% (1194) were identified as P. aeruginosa and 11% (171) as S. aureus. At
8 mg/L meropenem inhibited 89% of all P. aeruginosa strains isolated, compared with
67% and 65% for ceftazidime and imipenem, respectively, at the same concentration. At
concentrations of 0-5 mg/L meropenem still inhibited 49% of these strains whereas
ceftazidime only inhibited 3%. At 4 mg/L, meropenem inhibited 100% of the S. aureus
strains compared with 59% for ceftazidime.

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Both meropenem and ceftazidime were well tolerated with no reports of nausea and
vomiting, even following bolus injection and no patients were withdrawn from the study
due to adverse events.
Transient elevations of liver transaminases were the most common biochemical
changes, seen in 13 meropenem and four ceftazidime patients for serum glutamic pyruvic
transaminase (ALT) and four versus one for serum glutamic oxaloacetic transaminase
(AST). Other changes were rare and minor.
The mean increase in AST from pre-therapy to the end of therapy was 9 IU/L in
both treatment groups. Mean ALT increases were 24 and 9 IU/L for meropenem
and ceftazidime, respectively. However these mean changes included one patient in the
meropenem group with known pre-existing liver disease who received the drug on three
occasions. Excluding his results, the mean increase on meropenem was 11 IU/L. In
repeated use over several courses, there were no long term effects and each elevation was
transient.

Discussion
Meropenem at a dosage of 75 mg/kg/day was found to be effective in the treatment of
acute exacerbation of lung disease in cystic fibrosis and as routine anti-pseudomonal
therapy. It appears to be at least as effective as ceftazidime in terms of overall clinical
response, improvement of lung function tests and reduction of bacterial load.
In cases where ceftazidime and other drugs have failed or have not been well tolerated,
or where organisms have been resistant, meropenem has proved effective, and dosages
up to 2 g 8-hourly in adults have been well tolerated (Knight & Pillai, 1993). Physicians
treating cystic fibrosis tend to use high doses of antibiotics. Meropenem has been well
tolerated, even in the successful treatment of pseudomonas meningitis in an
immunocompromised patient treated with 2 g 8-hourly for 18 weeks (Donnelly el al.,
1992).
In cystic fibrosis, the ease of antibiotic administration is important, especially in the
treatment of young children, and intravenous therapy given in the home can allow them
the freedom to attend school regularly (David, 1986, 1989). Attendance at a hospital for
serum aminoglycoside monitoring is a significant drawback. Meropenem may be given
as a short intravenous infusion or as an intravenous bolus injection either directly into
the vein or through a line or implanted access device. This facilitates self-administration
by older compliant patients, allowing home therapy.
Following completion of the randomised study, five patients who successfully received
meropenem have received a further 15 courses on a named-patient basis. When the study
and named-patient experience are considered together, three patients have in total
142 S. Byrne et al.

received five, seven and eight courses. These have been well tolerated and so far, we have
only seen occasional resistant isolates after therapy. These isolates have reverted to
sensitivity, allowing re-treatment.
It appears that meropenem offers a new alternative for the treatment of P. aeruginosa
respiratory tract infections in cystic fibrosis. In our experience, it has been well tolerated
by patients and easy to administer.

Acknowledgements
The results in this study were presented in part as a poster at the Eighteenth European

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Cystic Fibrosis Conference, Madrid, Spain, 1993 (abstract PD40). Grateful thanks to the
nursing and pharmacy staff at the respective hospitals and Suzanne Martin and Keith
Williams of Zeneca Pharmaceuticals for provision of materials and co-ordination of the
study. We acknowledge the help of Dr P. J. Turner of Zeneca Pharmaceuticals in
performing the MIC studies.

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