Download Sequential Intravenous-Oral Administration of

Sequential
Intravenous-Oral
Administration
of Ciprofloxacin
vs Ceftazidime
in Serious
Bacterial Respiratory Tract lnfections*
Faroque
A. Khan,
MB.,
F.C.C.P;t
and
Riyad
M.D4
Basir,
The ethcacy
and safety
of sequential
intravenous/oral
ciprofloxacin
in rnoderate
to severe respiratory
tract infections (RTI) were cornpared
with those of ceftazidirne
in a
prospective
clinical
trial.
Sixty-six
patients
received
IN
ciprofloxacin
(200
to 300
rng twice
daily),
followed
by oral
rng twice daily). Fifty-six patients received
intravenous
ceftazidime
(1 to 2 g two to three times daily).
Ciprofloxacin
was as effective
as ceftazidime
and produced
a 91 percent clinical cure rate. Signfficantly
more pretreatment bacterial
isolates
were susceptible
to ciprofloxacin,
and ciprofloxacin
had a significantly
higher
rate of sputum
bacterial
eradication
than did ceftazidime.
Ciprofloxacin
ciprofloxacin(500
T
he
recent
introduction
represents
a major
of
advance
potent
in the
antibiotics,
allowing
for the first
therapy
of serious
infections
caused
tant bacteria.
tive
in terms
compounds
ciprofloxacin
of its potency,
rapidity
RTlrespiratory
available
the most
ofbacterial
infections;
tract
of
oral
resis-
MIC
minimal
inhibitory
concentration
PATIENTS
development
time
effective
by multiply
currently
is among
broad
minimal
low
4-quinolones
Four fluoroquinolones,
as follow, are in various
stages
of approval
and clinical
investigation
in the United
States
norfioxacin,
ciprofloxacin,
enoxacin,
and ofloxacm.’
Of the
investigation,
in vitro antibacterial
activity with particularly
inhibitory
concentrations
for Gram-negative
organisms.
Ciprofloxacin
was well tolerated;
there were few
adverse
effects.
Ciprofloxacin
was an effective
and welltolerated
treatment
for severe RTI that had the advantages
of broad in vitro antibacterial
activity,
twice-daily
dosing,
and sequential
availability
in an intravenous
and oral
formulation.
(Chest
1989; 96:528-37)
showed
AND
METHODS
Patients
hospitalized
at Nassau County Medical
Center
between
and June 1988 for community-acquired,
nursinghome-acquired,
hospital-acquired
(more than 72 hours of hospitalization) bacterial
respiratory
tract infections
were enrolled
in the
study. Bacterial
lower respiratory
tract infection
was defined
as
January
1987
presumedifpatients
fever
over
hadcompatible
37.2#{176}C,total
clinical
white
blood
cell
features
count
which
over
included
10,000/cu
mm,
and productive
cough with purulent
sputum,
or proven if patients
had, in addition,
a positive sputum culture from a sputum which on
Cram
stain had less than 25 squamous
epithelial
cells and 25 or
under
attrac-
more
killing
neutrophils
considered
per
to be
low-power
suitable
field.
All
for intravenous
these
patients
antimicrobial
were
treatment.
of the 140 patients
had normal chest roentgenogram;
remaining
129 patients
had roentgenographic
findings ranging
bronchopneumonia
to multilobar
pneumonia.
All patients
the
from
Eleven
For
and
that
editorial
see
page
453
In vitro
pharmacokinetics.
ciprofloxacin
Gram-negative,
well as organisms
comment
is
active
studies
have
shown
against
Gram-positive,
and multi-drug-resistant
such as Chlamydia,
and Legionella.25
We have previously
results
of a prospective,
double-blind,
assess
the safety
and efficacy
of oral
bacteria,
Mycobacteria,
this
study,
we
report
our
results
with
the
informed
clinical
features
as
dl,
group.
ofage,
Antibiotic
comparison
of sequential
intravenous/oral
ciprofloxacin
with intravenous
ceftazidime
in the treatment
of hospitalized
patients
with lower
respiratory
tract infections.
venous
528
were
excluded
findings)
included
if they
were
if their
was more
condition
was
gave
compatible
were
value
psychiatric
had
x-ray
result
creatinine
and an
in the
under
18
2 mg/
than
hemodynanii-
disease.
administered
ceftazidime,
minimum
in
randomized
a sequential
code.
One
manner
group
with
received
a
intra-
a day, except
for five patients
day; and the control
group
received
1 to 2 g two to three
times a day intravenously.
A
of five days of therapy
was required
for evaluation.
No
ciprofloxacin,
200
300
mg
mg
twice
other
patient
received
as the control
drug
that ofciprofloxacin.
antibiotics
parenteral
community-acquired
twice
a
chosen
prescribed
Medical
had
who
Administration
received
matched
0From
the
Department
of Medicine,
Nassau
County
Center,
East Meadow,
NY.
tProfessor
of Medicine.
fllesearch
Fellow.
Manuscript
received
July 5; revision
accepted
January
4.
Reprint
requests:
Dt Khan,
Department
of Medicine,
County
Medical
Center, East Meadou
NY 11554
were
and
or they
computer-generated,
who
stain
serum
to quinolones,
cally unstable
Antibiotics
In
Patients
patients
abnormal
Cram
pregnant,
allergic
Those
cough,
sputum
presumed
years
consent.
(fever,
unsatisfactory
reported
on the
clinical
trial to
ciprofloxacin
in
comparison
with those
of ampicillin
in the treatment
of mild
to moderate
respiratory
tract
infections.6
written
concomitanfly.
because
In addition,
antimicrobial
and
its
agent
hospital-acquired
in
Ceftazidime
vitro
it was
spectrum
the
for the
lower
most
was
closely
commonly
treatment
of both
respiratory
tract
infections.
Clinical Monitoring
Nassau
Laboratory
complete
tests,
blood
Treatment
cell
including
count,
of Serious
liver
were
Bacterial
Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21600/ on 05/12/2017
and
performed
renal
before
function
and after
tests
and
therapy.
Respiratory Tract Infections (Khan, Besir)
and
Pre-enroliment
patients.
Serum
receiving
that
drug
reaction;
fever,
cough,
follow-up
drug.
a daily
done
in
21
were
monitored
daily
ofthe
physical
examination
production
on
all
suction
were
Only
specimens
and
25 or more
mented
was
performed
for adverse
sputum
or
sputum
obtained
from
all
on all expectorated
containing
less
than
per
low-power
obtained
patients.
sputum
25 squamous
were
hours.
incubated
Isolates
Disk
inoculated
blood,
identified
isolates,
pretive
zone
using
criteria
for
Kirby-Bauer
ciprofloxacin
inhibitory
resistant
susceptible,
21 mm
concentrations
1-In
of
pneumoniae
E Coil
Enterobacter
Citrobacter
1
5
3
2
13
12
6
6
9
5
5
Bacterial
(p.g/ml)
Range
Mean
S
.008-.5
(.059)
38
17
.06-1
(.378)
23
-
5
.015-.
(.04)
5
-
-
-
2
.015-25
(.133)
4
-
-
15
-
10
.25-1
.5-2
(.55)
(1.75)
11
12
-
10
.25-2
(1.1)
10
-
4
.015-1
(.269)
5
-
-
-
2
.03-06
(.045)
4
-
-
3
.25-4
(1.58)
3
-
-
(.076)
1
-
1
1
-
1
2
-
5
-
-
2
2
-
-
2
.03-.
Morganella
2
2
-
-
2
.008-125
2
2
-
-
1
.25
(.067)
(.25)
5
4
-
-
3
.06-4
(1.52)
1
0Total number
of isolates.
of MICs.
number
One strain
liquifaciens.
ofeach
ofthe
following:
125
4
1
2
-
(.257)
(.103)
(7.3)
(2.03)
(21.33)
(.238)
(.475)
(.405)
(.5)
4-8
.
(6.67)
125-64
1-32
(32.06)
(16.5)
16
-
1
(16)
8-16
(13.33)
118t
170*
tTotal
(49)
-
2
Mean
(3.4)
-
9
Range
4-64
.06-.5
.006-125
.25-32
.06-4
8-64
.006-1
.125-2
.06-1
.5
6
3
Diffusion
3
(.018)
Acinetobacter
anitratus
Serratia marceseus
Inhibitory
(.804)
.008-03
-
2
(g/ml)
.06-8
3
5
or
.06-8
-
1
was
1
-
1
-
4
Pseudomonas
stutzeri
9Other Gram-negatives
-
R
-
4
morgani
I
26
125
failure
.
-
-
to
of infection
by Agar
-
12
-
isolates
Concentration
(Kirby-Bauer)
.
.
5
stuarti
as
Stan-
of previously
Clinical
MIC
(.057)
6
of
Minimum
.015-125
5
criteria
Ceftazidime
9
12
mirabilis
MIC
Strains
1
-
p.g/ml
Laboratory
and symptoms
-
3
Providencia
of signs
-
9
1.0
intermediate
disappearance
2
22
than
interpretive
of infection.
(1.67)
12
Ivteus
and
as the
symptoms
1-2
22
1.0 p.g/ml
for resistant
susceptibility
4
aureus
more
Clinical
-
pneumoniae
sp
and
No.of
R
-
jig/mI
MIC
Therapy
as the continuation
Testing-Ciprofloxacin
-
Strep
strep
and
the
were
2.0
was
tentative
considered
on
categorize
was defined
cure
signs
defined
MIC
-
Staph
3-Hemolytic
breakpoints
Sensitivity
23
were
were
Committee
ofAntibiotic
A clinical
were
.
9
to
Ciprofloxacin
The
than
values
p.g/ml
Sensitivity
38
sp
MIC
National
used
more
MIC
to 2.0
The
the
and
CEFF
25
sp
which
growth.
plates.
of antibiotic
with ciprofloxacin
therapy
Antibiotic
38
maltophilia
were
Evaluation
zone
antibiotics
I
inoculated
of antibiotic
powder.
CIPRO
S
were
concentration
ofvisible
Antibiotic
Isolates
the
with
ftaz’
inter-
(Kirby-Bauer)
Hemophilus
sp
PS
aeruginosa
for
series
lowest
standard
isolates
or equal
documented
No.of
by
and
inter-
or less,
Vitro
by
dards
or more.
(MICs)
Strains
detailed
in each
as the
for systemic
for susceptible
in susceptibility.
performed
Interpretive
15 mm
outlined
Plates
3
included
defined
a laboratory
but less than
18 to 24
Standard
2
ofthe
was no evidence
as
or less
methods.#{176}’#{176}
was
was
there
breakpoints
for
were
value
supplied
supple-
for
described
technique.”
were
and
dioxide
were
Table
Kieb
bacteria
MIC
at which
cells
agar
dilutions
as
Standards.
The
agar, and MacConkey
carbon
for ceftazidime
for ceftazidime
16 to 20 mm,
Minimal
testing
the
criteria
soy
chocolate
by previously
susceptibility
on all
mediate,
sheep
trypticase
at 35#{176}C
in 5 percent
were
diffusion
onto
technique
Laboratory
by
isolates.
were
dilution
Clinical
with a multipoint
replicator
designed
to deliver
a 1 p.1 inoculum
containing
approximately
10 organisms.
The plates
were
read at 24
and 48 hours. A control
plate without
antibiotics
was inoculated
before
and after each antibiotic
series,
and appropriate
quality
Gram
accepted
agar
for
the use oftwofold
specimens.
epithelial
field
the
Committee
of
and
was maintained.
neutrophils
with 5 percent
and
by
National
analysis.’
Specimens
Ps
determined
patients
control
expectorated
smears
size
were
monitored
Methods
tracheal-bronchial
agar
films
were
record
and sputum
Spontaneously
culture
x-ray
levels
All patients
and
Microbiologic
stain
chest
theophylline
CDC-M6,
Achroinohacter
xylosoxidaris.
Pseudonzonas
pseudoakaligenes.
Bordetella
Serratia
bronchosepta,
lnterpretatu)n:
1. Three
2.
The
3.
Eight
4. Three
5.
Four
strains shoved
in vitro resistance
MICc of Cipro for Gram negatives,
OUt
often
out
offour
out
of five
strains
strains
strains
to Cipro
ofpneumococci
of Pseudonionas
of enterohacter
6. Two strains of Staph aureus
S = sensitive;
I intermediate;
were
R
(1.77%)
were
tested
ofintermediate
were
maltophilia
aerogenes
resistant
compared
in general,
to Ceft
lower
tested
were
(MIC
resistant
more
to 14 strains
than
those
sensitivity
were
resistant
in the
for Gram
to Cipro
to Ceft
Ceft
positive
(MIC
(8.24%).
group
bacteria.
(MIC
of2
g/ml).
more
than
64).
to Ceft.
than
64) and
nine
strains
were
of intermediate
sensitivity
(MIC
16).
resistant.
CHEST
Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21600/ on 05/12/2017
I 96 I 3 I SEPTEMBER,
1989
529
Table
2-Characteristics
ofIztiente
with
in Whom
Pneumonia
Ciprofloxacin
Regimen
Failed
Cipro,
Dose,
Severity
Patient
of
No.
Age/Sex
Diagnosis
38
55/M
Pneumonia
Underlying
Disease
Infecting
Infection
Chronic
Cipro MIC
pg/ml
Route and
Duration
Not
200
Organisms
Severe
No pathogens
schizophrenia
done
isolated
mg
Comments
IV
Continuing
x 2 x 3 #{189} and
days
fever,
respiratory
symptoms.
Outcome:
responded
to benzyl
penicillin.
46
43/M
Pneumonia
Alcohol
abuse,
addiction,
in ‘85,
Staph aureus
Moderate
.5/S
drug
intravenous
HIV+
200 mg IV
x 2 x 3
Worsening
days
and
cryptococcal
meningitis
of clinical
signs of infection
switched
to
Bactrim,
in ‘85
erytliromycin,
nafacillin
and
B
amphotericin
Outcome:
128
73/F
Pneumonia
Recurrent
Enterobacter
P aeruginosa
Severe
episodes
ofpneumonia,
CVA,
aemgenes
.03/S
.25/S
died.
200 g IV
Patient
deteriorated
x 2 x 3 #{189}and WBC increased
days
to 28.9; switched
to
meziocillin
and
seizure
disorder,
urinary
tract infection
gentamycin.
Outcome:
died
patient
day of
on 4th
therapy.
133
34/M
Pneumonia
.
Severe
. .
No pathogens
isolated
Not
done
200
g
IV
Persistence
x 2x 5
days
of signs
and symptoms
infection.
Pneumocystis
of
carnii
pneumonia
diagnosed
by
bronchoscopy
and
switched
to IV
No risk
for AIDS.
Bactrim.
factors
Outcome:
recovered.
worsening
defined
of signs
as the
Bacteriologic
pathogen
sputum
analysis,
and
symptoms.
elimination
failure
Bacteriologic
ofpretreatment
was
defined
eradication
pathogens
as
persistence
of
was
from
sputum.
the
original
of a new pathogen
on posttreatment
cultures.
The chi-square
test was used in the statistical
and a p value ofless
than 0.05 was considered
statistically
and/or
isolation
significant.
RESULTS
Ofthe
140 patients
treated,
87 of these patients
produced
listed
in Table
1. The
18
ciprofloxacin
who
were
following
five days
group
and ten in the ceftazidime
not evaluable
were
eliminated
reasons:
failure
(14), confirmation
(two),
endocarditis
this
report
is based
patients
There
with documented
were 68 men and
of 58 years
(range
21
group)
for the
to take the drug for at least
ofother
diagnosis-tuber-
culosis
Thus,
530
122 were evaluable
and
170 bacterial
isolates
as
patients
(eight
in the
(one),
meningitis
on the
remaining
respiratory
54 women
to 95 years).
(one).
122
tract infections.
with a mean
age
Sixty-six
patients
received
ciprofloxacin
idime
for
a mean
and five
intravenous
days
and
duration
56 patients
received
of six days
of oral ciprofloxacin,
ceftazidime,
respectively.
significant
difference
groups
in age, gender,
between
admission
and
therapy.
In the 11 patients
seven
in ciprofloxacin
and
group,
the bacterial
isolates
rable
and
Pseudomonas
included
species
one
and
no
pathogens
were
ing
of
no
in
five,
aureus
isolated
in
three
isolates
was
found
Efficacy
A clinical
cure was achieved
in the proven
group
(91 percent)
group
days
was
with
acute
four
in the
were compa-
Hemophilus
influenza
in two, Staphylococcus
patients.
Similar
pattern
ofbacterial
in the patients
with pneumonia.
Clinical
seven
There
these
two patient
diagnosis,
or length
of antibiotic
bronchitis,
ceftazidime
in
ceftaz-
of intravenous
ciprofloxacin
(90 percent).
aid
This
in 42 of the 46 patients
with patients
receiv-
18 of the
20
in the
was not statistically
Treatment of Serious Bacterial Respiratory
Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21600/ on 05/12/2017
presumed
significant
Tract Infections (Khan, Basir)
Table
3-Characterietica
ofPatients
with
in Whom
Pneumonia
Ceftazidime
Regimen
Failed
Cell,
Severity
Dose,
of
Patient
No.
14
Age/Sex
Diagnosis
34i’M
Pneumonia
Underlying
Disease
Infecting
Infection
None
Severe
Cell
Organisms
Strep
MIC
Route
g/ml
pneumoniae
and
Duration
.25/S
ig
X
Comments
3 x 1
day
Worsening
fever
constitutional
chest
and
and
symptoms.
Outcome:
responded
to
erythromycin.
23
36,’M
Pneumonia
Seizure
disorder,
IVDA,
Severe
No pathogens
isolated
alcohol
2g x 3 x 6
Persistence
days
and
of fever
signs
and
symptoms
abuse
of chest
infection.
Responded
to
and
penicillin
gentamycin.
58
95/M
Pneumonia
COPD,
colon
cancer,
Alzheimer’s
disease,
Severe
partial
Strep pneumoniae,
Staph aureus
.25/S
ig x 3 x
Worsening
10 days
signs
of clinical
and
symptoms
with increasing
superinfection
WBC;
colectomy
changed
penicillin
to
and
gentamycin.
Outcome:
pneumonia
resolved.
139
79fF
Pneumonia
UT!
Recurrent
Severe
Ps aeruginosa
8/S
ig
After
with indwelling
IV x 3 x
response
catheter,
14 days
ofceftazidime,
Mzheimers
to 14 days
she
deteriorated
disease,
clinically
and
with
switched
to
in ‘77
naficillin,
dementia,
breast
initial
cancer
mastectomy
was
and
mezlocillin
gentamycin.
Outcome:
2 days
140
861M
Pneumonia
Colonic
polyps
colonoscopy
Severe
with
Hemophilus
influenzae
.
125/S
and
polypectomy
barium
died
ig
Worsening
signs
IV x 3 x 6
symptoms
with
days
fever,
by
diverticulosis
She
later.
enema
and
increased
WBC
and
worsening
chest
x-ray.
Died
while
on protocol.
Presumed
death:
cause
of
acute
myocardial
infarction.
from
the clinical
cure
rate
obtained
with
38 out of 42 in the proven
group
(90
out of 14 in the presumed
group
(85
of the patients
enrolled
were
adult
to a tertiary
care
county
hospital
respiratory
tract
infection
considered
severity
antibiotic
elderly
necessitating
therapy.
who also
hospitalization
A majority
had significant
ceftazidime-
marizes
percent)
and 12
percent).
All 122
patients
referred
for treatment
of
to be of a
and
parenteral
of the patients
comorbidities-dia-
were
betes,
hypertension,
ethanol
abuse,
etc. A clinical
and
bacteriologic
response
of over
90 percent
in both
ciprofloxacin
and ceftazidime
treated
patients
in this
group
of patients
is impressive.
Tables
2 and 3 sum-
the
clinical
patients
in whom
total of 66 patients
and
bacteriologic
features
either
regimen
failed.
in the ciprofloxacin-treated
Four
of the
out of a
group
failed
therapy.
Two patients
(46 and 133) had respiratory infection
in a background
of HIV disease.
One
patient
(128) was a failure.
This 73-year-old
man had
seizure
disorder,
recurrent
episodes
of pneumonia,
and
a polymicrobial
Gram-negative
tion. A fourth
patient
responded
to penicillin
(38) had
therapy.
respiratory
in the ceftazidime
group
failed
therapy.
(14 and 58) had
S pneumonia
which
penicillin.
One
(23) had no pathogens
CHEST
Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21600/ on 05/12/2017
infec-
no pathogens
and he
Five ofthe
56 patients
I 96 I 3 I
Two patients
responded
to
and
he re-
SEPTEMBER,
1989
531
sponded
to alternate
140),
failed
therapy.
both
elderly
ceftazidime
with
therapy.
Two
patients
multiple
(139
medical
and
ation
of
the
received
Bacteriologic
A total
Susceptibility
of 170 bacterial
isolates
were
recovered
from
pretreatment
sputum
cultures.
All these
isolates
showed
in vitro sensitivity
to ciprofloxacin,
except
for
four isolates
(one Pseudomonas
aeruginosa,
one Acinetobacter,
3-hemolytic
xylosoxidans
one Achromobacter
strep
sp which
diffusion,
but
was
was
sensitive
the
isolates,
ceftazidime
except
(three
Pseudomonas
aeruginosa,
by the
for
13,
MIC
showed
Pseudomonas
four
two
and
by
resistant
one
disc
method).
All
sensitivity
to
maltophilia,
one
Enterobacter
aero genes,
morganii,
one S mar-
S aureus,
one Morganella
one Citrobacter
diversus).
Twenty-two
patients
in the ciprofloxacin
and 18 patients
in the ceftazidime
treatment
group
had more
than
one isolate
in their
sputum
culture
. This
sterilization
of sputums
Microbiologic
Results
in
one
patient;
ceftazidime,
not observe
any
tween ciprofloxacin
who
received
following
patient
adverse
clinically
significant
and theophylline
both
effects
drugs
in this
interaction
bein the 21 patients
therapy.
Superinfrctions
Three
of
developed
tiple
66
patients
underlying
three
in
superinfection.
medical
eventually
died
56 patients
the remaining
patients
are
the
ciprofloxacin
All three
patients
problems
and
from
the
group
had
two
mulof the
superinfection.
in the ceftazidime
one died from
this
superinfection;
did not appear
to
in either
group.
the
another
cramps
and diarrhea
Of the 56 patients
who
were
noted:
seizures
(one),
hallucinations
(one),
progressive
decrease
in WBC
(one). Ceftazidime
was not
discontinued
in any of these
three
patients.
We did
the
cescens,
pretreatment
influence
the
drug
developed
transient
abdominal
while
receiving
ciprofloxacin.
problems,
of
Six
group
developed
superinfection
and
five recovered.
The
summarized
in Tables
highlights
4 and 5.
of these
DISCUSSION
Table
Oral
1 summarizes
recovered
in
the
the
87
type
and
patients,
number
as
of isolates
well
as
the
disk
tory
susceptibility
for these
isolates
and the available
values
of 118 isolates.
Significantly
more isolates
MIC
were
results
susceptible
determined
as
MIC
tory
values
to ciprofloxacin
by the diffusion
reveal
that
than
to ceftazidime
technique.
The
ciprofloxacin
vitro
than
ceftazidime
negative
bacteria
tested.
was
more
active
in
against
the strains
of GramAll nine of the Enterobacter
isolates
were
susceptible
to ciprofloxacin
at a concentration
equal
to or less than 0.06 pg/ml,
while
four of
these
nine isolates
were resistant
to ceftazidime.
The
MIC
values
aeruginosa
Ciprofloxacin
isolates
of ciprofloxacin
species
range
was
more
MIC
of Streptococcus
isolates
susceptible
susceptible
to ciprofloxacin.
in the ciprofloxacin
group
in the ceftazidime
group
the end of the treatment.
antibiotic
ated by both
encountered
who
532
All the
isolates
were
with
ceftazidime
12 of 12 of the
and nine
of 12
Three
of the 46 patients
and three
of the 41 patients
had organisms
persisting
at
Reactions
Both
received
regimens
patient
were
groups.
skin rash
ciprofloxacin,
were
of the
generally
well-toler-
The common
in five of the
side effects
66 patients
necessitating
discontinu-
been
found
of various
infection.
to
be
forms
Contrary
to
quite
of respira-
the
favorable
problems
were
due
to resistance
or recurrence
of streptococcal
pneumonia
infection
or failure
to
eradicate
Pseudomonas.
We also reported
on a large,
prospective,
double-blind,
we compared
ciprofloxacin,
ampicillin
in the treatment
tract
randomized
study
where
750 mg twice a day, with
of bacterial
respiratory
Eight-seven
clinical
bacterial
(p value
against
has
treatment
found
by Gleedhill
et al and Kobayashi,’’5
16 in his
study of oral ciprofloxacin
for respiratract infection,
reported
several
problems;
most
ceftazidime
isolates
of Staphylococcus
aureus
to ciprofloxacin.
Ceftazidime
was
ciprofloxacin
against
the 12 isolates
to
tract
ciprofloxacin
(MIC
less than
1 pg/ml),
to or less than
.008 pg/ml
pneumoniae,
in the
the Pseudomonas
.06 to 1 .0 jig/ml.
than
influenzae.
to ciprofloxacin
range
equal
to 0.5 p.g/ml.
The
tested
were sensitive
more effective
than
Adverse
from
active
ofHemophilus
susceptible
with an
for
ciprofloxacin
effective
effective
as
or oral
ampicillin
patients
cure
rate . Significantly
isolates
were
susceptible
of less than
0.05),
and
significantly
tion
than
higher
ampicillin
Ciprofloxacin
tivity with
showed
particularly
trations
for
was well
tolerated;
received
ampicillin.
Ciprofloxacin
and produced
a 98
rate
either
was as
percent
more
pretreatment
to ciprofloxacin
ciprofloxacin
had
a
of sputum
bacterial
eradica(p values
of less
than
0.05).
broad
in vitro antibacterial
aclow minimal
inhibitory
concen-
Gram-negative
there
organisms.
were
few adverse
Ciprofloxacin
effects,
and
patients
had a significantly
lower incidence
of diarrhea
with ciprofloxacin
than with ampicillin
(p value of less
than
and
that
0.05).
We felt that ciprofloxacin
was an effective
well tolerated
treatment
for bacterial
bronchitis
had the advantage
of broad
in vitro antibacterial
activity
and
ciprofloxacin,
twice
we
daily dosing.6
did encounter
ciprofloxacin
and theophylline,
larly seen in elderly
patients
term theophylline,
and who
and this was particuwho had been
on longreceived
the total dose of
Treatment of Serious Bacterial Respiratory
Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21600/ on 05/12/2017
In the study
of oral
interaction
between
Tract Infections
(Khan,
Basir)
Table
4-Characteristics
with
ofPatients
on Ceftazidime
Pneumonia
Who
Developed
Superinfection
Cell,
Severity
Patient
No.
Age/Sex
Diagnosis
Underlying
Disease
43
86/F
Pneumonia
Carcinoma
aureus
Staph
of
Infecting
Infection
Organisms
of
P
Dose,
Cell
MIC
Severe
uterus,
aeruginosa
hysterectomy
Route
p.g/ml
and
Duration
Comments
8/S
lg IVQ8
Developed
21S
10 days
bacteremic
1965, anemia,
chronic diarrhea
of
unknown
etiology
41
66/M
Acute
Chronic
superinfection.
Outcome:
Severe
bronchitis,
H
parainfluenzae
.03/S
lg IVPBQ8
emphysema
exacerbation
Strep
frcalLs
in
died.
Improvement.
8 days
Developed
of COPD
with
superinfection
Pseudomonas
aeruginosa,
PS
maltophila.
Outcome:
recovered.
48
23/M
Pneumonia
None
Severe
No pathogens
2g IVPBQ8
5 days
-
Improvement.
Developed
superinfection
with
influenzae.
H
Outcome:
recovered.
52
56t’M
47/F
32
S/P aortofemoral
Pneumonia
Pneumonia
bypass
graft,
alcohol
abuse
Sarcoidosis
No pathogens
Moderate
H
-
Parainfluenzae
.008/S
during
diagnosed
current
Moderate
ig IVPQ8
6 days
Improvement.
Superinfection
with
E coli. Outcome:
recovered.
ig IVPBQ8
Improvement.
Candida
4 days
albicans
superinfection.
admission
for pneumonia
58
95/M
Pneumonia
COPD,
cancer
colon
with
Severe
pneumonia
Strep
10 days
lg IVPBQ6
Worsening
right
signs
symptoms
with increased
hemicolectomy,
Alzheimer’s
of clinical
and
disease
WBC,
Staph
aureus
superinfection
sputum.
in
Switched
to
and
penicillin
gentamycin.
Outcome:
pneumonia
resolved.
1 ,500
mg
ciprofloxacin
a
We have
on the effectiveness
ment
of 14 adult
of oral ciprofloxacin
patients
with bacterial
These
received
14 patients
also
reported
treatment
bronchitis
in the treatpneumonia.
750 mg of ciprofloxacin
for
a duration
of 11.5 days. Thirteen
had underlying
lung
disease,
and 12 of the 14 (86 percent)
were cured.
All
the isolates,
which
included
streptococcal
pneumonia
in five,
Hemophilus
floxacin
and
only
in four,
two
were
pathogens
sensitive
persisted
this
of whom
19 had bacterial
isolates
from
sputum
blood,
and all patients
improved
in this study.
Based
evident
on an analysis
of the
that
oral
ciprofloxacin
or
reported
studies,
it is
is effective
in the
infection,
both
Fibrosis
ment
ciprofloxacin
of patients
floxacin’s
special
nosa,
S aureus,
Ernst
et al also reported
on the effectiveness
mg twice a day in 25 patients
with pneumonia,
19
of 750
tract
A number
of studies
have reported
on the effectiveness of oral ciprofloxacin
in the treatment
of bacterial
infection
in cystic fibrosis.21
Oral
to ciproin
Cystic
of bacterial
respiratory
as well as pneumonia.
is of special
with
cystic
activity
against
and Hemophilus
pathogens
which,
tions
in patients
lies in safety,
oral
tient
use.
Some
not
with
interest
fibrosis
influenzae,
bioavailability,
studies
show
Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21600/ on 05/12/2017
I 96 I 3 I
and
the
cause
The
treat-
of cipro-
Pseudomonas
uncommonly,
cystic
fibrosis.
CHEST
in the
in view
the
aerugithree
exacerbaattraction
possible
outpaemergence
of
SEPTEMBER,
1989
533
Sequential
Intravenous-Oral
Administration
of Ciprofloxacin
vs Ceftazidime
in Serious
Bacterial Respiratory Tract lnfections*
Faroque
A. Khan,
MB.,
F.C.C.P;t
and
Riyad
M.D4
Basir,
The ethcacy
and safety
of sequential
intravenous/oral
ciprofloxacin
in rnoderate
to severe respiratory
tract infections (RTI) were cornpared
with those of ceftazidirne
in a
prospective
clinical
trial.
Sixty-six
patients
received
IN
ciprofloxacin
(200
to 300
rng twice
daily),
followed
by oral
rng twice daily). Fifty-six patients received
intravenous
ceftazidime
(1 to 2 g two to three times daily).
Ciprofloxacin
was as effective
as ceftazidime
and produced
a 91 percent clinical cure rate. Signfficantly
more pretreatment bacterial
isolates
were susceptible
to ciprofloxacin,
and ciprofloxacin
had a significantly
higher
rate of sputum
bacterial
eradication
than did ceftazidime.
Ciprofloxacin
ciprofloxacin(500
T
he
recent
introduction
represents
a major
of
advance
potent
in the
antibiotics,
allowing
for the first
therapy
of serious
infections
caused
tant bacteria.
tive
in terms
compounds
ciprofloxacin
of its potency,
rapidity
RTlrespiratory
available
the most
ofbacterial
infections;
tract
of
oral
resis-
MIC
minimal
inhibitory
concentration
PATIENTS
development
time
effective
by multiply
currently
is among
broad
minimal
low
4-quinolones
Four fluoroquinolones,
as follow, are in various
stages
of approval
and clinical
investigation
in the United
States
norfioxacin,
ciprofloxacin,
enoxacin,
and ofloxacm.’
Of the
investigation,
in vitro antibacterial
activity with particularly
inhibitory
concentrations
for Gram-negative
organisms.
Ciprofloxacin
was well tolerated;
there were few
adverse
effects.
Ciprofloxacin
was an effective
and welltolerated
treatment
for severe RTI that had the advantages
of broad in vitro antibacterial
activity,
twice-daily
dosing,
and sequential
availability
in an intravenous
and oral
formulation.
(Chest
1989; 96:528-37)
showed
AND
METHODS
Patients
hospitalized
at Nassau County Medical
Center
between
and June 1988 for community-acquired,
nursinghome-acquired,
hospital-acquired
(more than 72 hours of hospitalization) bacterial
respiratory
tract infections
were enrolled
in the
study. Bacterial
lower respiratory
tract infection
was defined
as
January
1987
presumedifpatients
fever
over
hadcompatible
37.2#{176}C,total
clinical
white
blood
cell
features
count
which
over
included
10,000/cu
mm,
and productive
cough with purulent
sputum,
or proven if patients
had, in addition,
a positive sputum culture from a sputum which on
Cram
stain had less than 25 squamous
epithelial
cells and 25 or
under
attrac-
more
killing
neutrophils
considered
per
to be
low-power
suitable
field.
All
for intravenous
these
patients
antimicrobial
were
treatment.
of the 140 patients
had normal chest roentgenogram;
remaining
129 patients
had roentgenographic
findings ranging
bronchopneumonia
to multilobar
pneumonia.
All patients
the
from
Eleven
For
and
that
editorial
see
page
453
In vitro
pharmacokinetics.
ciprofloxacin
Gram-negative,
well as organisms
comment
is
active
studies
have
shown
against
Gram-positive,
and multi-drug-resistant
such as Chlamydia,
and Legionella.25
We have previously
results
of a prospective,
double-blind,
assess
the safety
and efficacy
of oral
bacteria,
Mycobacteria,
this
study,
we
report
our
results
with
the
informed
clinical
features
as
dl,
group.
ofage,
Antibiotic
comparison
of sequential
intravenous/oral
ciprofloxacin
with intravenous
ceftazidime
in the treatment
of hospitalized
patients
with lower
respiratory
tract infections.
venous
528
were
excluded
findings)
included
if they
were
if their
was more
condition
was
gave
compatible
were
value
psychiatric
had
x-ray
result
creatinine
and an
in the
under
18
2 mg/
than
hemodynanii-
disease.
administered
ceftazidime,
minimum
in
randomized
a sequential
code.
One
manner
group
with
received
a
intra-
a day, except
for five patients
day; and the control
group
received
1 to 2 g two to three
times a day intravenously.
A
of five days of therapy
was required
for evaluation.
No
ciprofloxacin,
200
300
mg
mg
twice
other
patient
received
as the control
drug
that ofciprofloxacin.
antibiotics
parenteral
community-acquired
twice
a
chosen
prescribed
Medical
had
who
Administration
received
matched
0From
the
Department
of Medicine,
Nassau
County
Center,
East Meadow,
NY.
tProfessor
of Medicine.
fllesearch
Fellow.
Manuscript
received
July 5; revision
accepted
January
4.
Reprint
requests:
Dt Khan,
Department
of Medicine,
County
Medical
Center, East Meadou
NY 11554
were
and
or they
computer-generated,
who
stain
serum
to quinolones,
cally unstable
Antibiotics
In
Patients
patients
abnormal
Cram
pregnant,
allergic
Those
cough,
sputum
presumed
years
consent.
(fever,
unsatisfactory
reported
on the
clinical
trial to
ciprofloxacin
in
comparison
with those
of ampicillin
in the treatment
of mild
to moderate
respiratory
tract
infections.6
written
concomitanfly.
because
In addition,
antimicrobial
and
its
agent
hospital-acquired
in
Ceftazidime
vitro
it was
spectrum
the
for the
lower
most
was
closely
commonly
treatment
of both
respiratory
tract
infections.
Clinical Monitoring
Nassau
Laboratory
complete
tests,
blood
Treatment
cell
including
count,
of Serious
liver
were
Bacterial
Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21600/ on 05/12/2017
and
performed
renal
before
function
and after
tests
and
therapy.
Respiratory Tract Infections (Khan, Besir)
not
encounter
and
theophylline.
any
dose-related
1,000
interaction
We now
and
feel
encountered
mg ofciprofloxacin
The
in the
ciprofloxacin
that
this
interaction
only
when
observed
group
and
group
more
is not
in the three
the six patients
surprising.
Potent
bial therapy
in elderly,
debilitated,
been
associated
with superinfection
ganisms,
and
the present
study
finding.27
The
role
of ciprofloxacin
infections
by Gram-positive
than
antimicrohas
orthis
treatment
particularly
Streptococcus
pneumonia,
had not been
fully
lished,
the doubt
arising
from
the laboratory
vation
of high
MICs.
We have
also observed
of
estabobserhigh
are
perhaps
related
to the
ciprofloxacin
in penetrating
four quinolones,
enoxacin,
ofloxacin,
have
the bronchial
in the lung,
sputum.
received
Ten
over
unique
properties
successive
et
oral
period.
2.2 ± 1 .3 mg(L
at two
mgfL
.6 ± 0.4
The
hours
ratio
was
the
same
ciprofloxacin
al
dose
samples
a 12-hour
of penetrating
studied
of 500
of the
21
mg
sputum
The
serum
hours
and
at six hours.
into
The
the
patients
who
ciprofloxacin.
were
levels
collected
peaked
decreased
slowly
corresponding
to bronchial
author
into
fluid
at six hours.
reported
the lung
distribution
also achieved
on the
parenchymal
a peaked
ratio of 300 to 900
a high concentration
pleural
level
administration
ofciprofloxacin
after
24 hours.m
Schlenkhoff
levels
In another
penetration
tissue.
to
nine
hours
at two
study,
of
Intra-
hours
before
tissue
showed
that the penetration
lung tissue
is marked
with
sampling
and
the
1. 1 to 17.32
mg/g.
into bronchial
to be quite
mucosa
variable.
low, the
The
bronchial
studied
plasma
500
mg
each,
average
mucosa
mg
The bronchial
levels.
limed
after the final
penetration
levels
equilibrium
dose
ofthe
are very
ratio
mucosa
was
absolute
drug
was found
levels
are
high.
Marlin
of enoxacin
in patients
established.
bronchial
of enoxacin
mucosal
at three,
and
the
high-pressure
beafter
They
mucosal
also
concentra-
was
given
biopsies
and
four, or five
samples
liquid
were
samples
were
in six patients
assayed
for
chromatography.
patients
was 117 (47.8 pg/g);
tration
was 3. 1 (1 . 1 pg/ml),
46.8.
These
data
suggest
into
the
enoxacin
Marlin
respiratory
mucosa,
tract.
These
and
by
et
al32
mucosa
of dose.
for all
the mean plasma
and the mean
the
possibility
bronchial
of
400
a
to all 18 patients.
plasma
hours
concluded
that equilibrium
between
bronchial
and plasma
is achieved
within
three
hours
The
mean
bronchial
mucosal
concentration
concenratio was
of active
avid
tissue
may account
for
quinolones
in the
findings
support
the
use ofciprofloxacin
in severe
chest infections
and help
to dispel
the earlier
apprehension
about
the use of the
medication,
particularly
in patients
who have streptococcal
pneumonia
infections.
It thus appears
that the quinolones
far exceed
all
the other known and studied
antibiotics
in their unique
property
of tissue
penetration,
particularly
into the
respiratory
tract.
This unique
feature
helps
to understand
with
the apparent
ciprofloxacin
infection
exceeding
the corresponding
serum
concentration.
These
authors
found
a lung-serum
ratio of 195 to 753
percent
at one hour, 545 to 1044 percent
in two hours,
bron-
500
was 161 percent
but
Although
the sputum
the distribution
and bronchial
the
Bronchial
obtained
infection.
results
received
tion achieved
with
the in vitro bacterial
activity
enoxacin.
Eighteen
patients
received
enoxacin,
mg twice
daily, for four days; on the fifth morning,
after
of ciprofloxacin
into the
the tissue
level significantly
percent
the
dose.
In the 15 patients,
the serum
levels ranged
from
1 to 9 .Lg/L while the bronchial
levels ranged
between
pg/ml
on 14
patients
who
had been
premedicated
with
100 mg
intravenous
ciprofloxacin
prior
to thoracic
surgery.
Four groups
received
injections
one, two, three,
and
four
had
ciprofloxacin
twice
daily for four days.
biopsy
samples
were
assayed
for the
biopsies
and venipunctures
were done
bronchial
given
and surgical
The lung tissue
serum
level with a
and averages
0.9
et al#{176}
reported
who
binding
to the tissue
macromolecules
the extensive
accumulation
of the
percent.
Ciprofloxacin
in the pleural
fluid
six
15 patients
transport
bron-
to 1000
800
et ala’ studied
at
.5 mg(L at two hours
and they stayed
six hours with a range of 0.5 to 0.8 mgfL.
0. 19 to 0.95
and
to
were
of serum
in
compared
of the
high concentrations
mucosa,
and in
venous
100 mg ciprofloxacin
was
samples
of the lung were
obtained.
level exceeded
the corresponding
with
property
level
hours,
Honeybourne
distribution
tissue compartments.
The
pefloxacin,
ciprofloxacin,
lining and achieving
in the bronchial
Bergogne
a single
chial levels
stable
until
unique
in three
hours.
et al32
tween
MICs
in our previous
study
and
the study
being
reported
here.
However,
our clinical
results
in the
seven
patients
who
received
ciprofloiacin
indicated
that the high MICs
did not interfere
with the action
of the drug.
The reasons
for this interesting
observation
in four
chial
patients
in the
sick people
with various
also confirms
and
the
bacteria,
percent
675
is
is used.
superinfection
ciprofloxacin
ceftazidime
between
Almost
have
paradox
in the
in the treatment
100
been
patients
treated
results
obtained
of S pneumonia
with
with
S pneumonia
ciprofloxacin,
a clinical
cure
rate
of over
95 percent
the relatively
high
MICs
in these
patients.
high
lung
achieved
marginal
explain
parenchymal
with
MIC
the
and
ciprofloxacin
level against
excellent
results
bronchial
apparently
S pneumonia
reported
in
with
spite
of
The very
tissue
levels
overcome
the
and help to
by
several
au-
Cost Analysis
Intravenous
ciprofloxacin
CHEST
Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21600/ on 05/12/2017
or
another
I 96 I 3 I SEPTEMBER,
comparable
1989
535
intravenous
quinolone
by federal
drug
the intravenous
However,
has,
agency,
preparation
comparable
as yet,
not
and
thus,
is not
cost
analysis
been
approved
the market
available.
oforal
cost
of
IV every
eight
hours.
Ciprofloxacin
was
mg orally
in both
mately
rable
clinical
results
The
daily
cost
in
11.5 days and
both
groups.
the
given
every
groups
to 24
mise
with
ciprofloxacin,
have been
realized
in clinical
to the
ofparenteral
therapy
would
storage!preparation/administration,
have
the
on
mg
ceftazidime
an average,
followed
by
twice
daily.
at
seven
various
The
Nassau
daily
costs
etc),
and
ther
that
ciprofloxacin
found
useful
in the
will
play
would
also
respiratory
tract
infections
abusers
who have a higher
be of use
in the
in diabetics
propensity
treatment
floxacin
536
After
becomes
the
intravenous
available,
it will
be
an
attractive
Chemother
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Mayo
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in
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ciprofloxacin,
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daily
in the ceftazidime
one extra
day of
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major role in the treatment
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ACKNOWLEDGMENTS:
house
staff
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spectrum
oral antibiotics
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patients,
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average,
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ciprofloxacin,
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S aureus
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ofthe
same drug
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which
cost
tract
organisms,
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the
Our study
demonstrates
that
works as effectively
as a potent
a total
savings
of
without
any compro-
saved,
respiratory
formulation
the first
1 Walker
dollars
for
Gram-negative
infections.
improves,
for those
hospitalized
suitable
for parenteral
12 hours.
The
was approxi-
efficacy.
In addition
therapy
considered
therapy,
by
polymicrobial
caused
totaled
$59 per day compared
to approximately
$9.00
per day for ciprofloxacin,
and the cost savings
of $50!
day or $579!total
course
oftherapy
could be achieved.
If the 32 patients
who had received
cefotaxime
had
been
treated
$18,000
could
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antimicrobial
ciprofloxa-
cm with other
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oral
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