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Antimicrobial Agents and Chemotherapy, January 1998, p. 194-196, Vol. 42, No. 1
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Microbiologic Efficacy of Azithromycin and Susceptibilities to
Azithromycin of Isolates of Chlamydia pneumoniae from
Adults and Children with Community-Acquired Pneumonia
Patricia M.
Roblin and
Margaret R.
Hammerschlag*
Departments of Pediatrics and Medicine, State
University of New York Health Science Center at Brooklyn, Brooklyn,
New York
Received 23 June 1997/Returned for modification 2 September
1997/Accepted 16 October 1997
 |
ABSTRACT |
Chlamydia pneumoniae was eradicated from the
nasopharynges of 26 of 33 (78.8%) evaluable children and adults with
community-acquired pneumonia who were treated with azithromycin. We
tested 55 isolates of C. pneumoniae obtained from 46 of these patients against azithromycin. The MIC at which 90% of the
isolates were inhibited and the minimal chlamydiacidal concentration at
which 90% of strains tested were killed of azithromycin
for these isolates were both 0.5 µg/ml. Seven patients remained
culture positive after treatment. The MICs of azithromycin for isolates
from two patients increased fourfold after therapy. However, all the
patients with persistent infection improved clinically. Further studies
of treatment of C. pneumoniae infection, utilizing culture,
are needed both to assess efficacy and to monitor for the possible
development of antibiotic resistance.
| |
TEXT |
Chlamydia pneumoniae is a
frequent cause of community-acquired respiratory tract infections,
including pneumonia and bronchitis (2, 4). Although
macrolides are frequently recommended as first-line drugs for treatment
of C. pneumoniae infection, there are limited data on the
use of these antibiotics. Practically all previously published
treatment studies have used serology only; thus, microbiologic efficacy
could not be assessed (1, 3, 11-13). One multicenter
treatment study of community-acquired pneumonia in children found the
efficacies of clarithromycin and erythromycin for eradicating C. pneumoniae from the nasopharynx to be 79 and 86%,
respectively (2). Persistence of the organism was not
associated with the development of antibiotic resistance in vitro
(10). Azithromycin is also active against a wide range of
organisms responsible for community-acquired pneumonia and has
pharmacokinetics and tolerance superior to those of erythromycin. Preliminary studies from our laboratory have demonstrated that azithromycin has in vitro activity against C. pneumoniae
similar to that of erythromycin (6). As part of two
nationwide, multicenter studies, which evaluated a 5-day course of oral
azithromycin for the treatment of community-acquired pneumonia in
adults and children, we performed in vitro susceptibility testing of
azithromycin against isolates of C. pneumoniae from these
patients.
Adult pneumonia treatment study.
Patients 12 years of age or
older presenting with community-acquired pneumonia were enrolled in the
study. Inclusion criteria included radiographic evidence of pneumonia,
no history of allergy to macrolide antibiotics, and no serious
underlying disease. This was an open, noncomparative, multicenter study
evaluating 1.5 g of azithromycin given orally over 5 days. Samples
from patients were cultured at baseline and at 10 to 14 days and 6 weeks after the initiation of treatment.
Pediatric community-acquired pneumonia treatment study.
Children 6 months through 16 years of age presenting with
community-acquire pneumonia were enrolled in the study. Inclusion criteria included radiographic evidence of pneumonia, no history of
allergy to macrolide antibiotics, and no serious underlying disease.
The children were randomized (2:1) to receive pediatric suspensions of
either azithromycin or the comparative agent (amoxicillin-clavulanate if <5 years of age or erythromycin if 
5 years of age). The dosage of
the azithromycin suspension was 10 mg/kg of body weight once on day 1 (maximum, 500 mg) followed by 5 mg/kg once daily (maximum, 250 mg/day)
on days 2 to 5. The amoxicillin-clavulanate suspension was given at a
dosage of 40 mg/kg per day, in three divided doses for 10 days, and the
erythromycin estolate suspension was given at a dosage of 40 mg/kg per
day, in three divided doses for 10 days. Samples from patients taken at
baseline and at 15 to 19 days after the initiation of treatment were
cultured.
Nasopharyngeal swab specimens were obtained for C. pneumoniae culture. Azithromycin (Pfizer) and erythromycin were
supplied as powders and were solubilized according to the instructions of the manufacturer. Culture of C. pneumoniae was performed
at SUNY Health Science Center at Brooklyn by utilizing
cycloheximide-treated HEp-2 cells grown in 96-well microtiter plates
(9). After 72 h of incubation all specimens were
passaged once. Cultures were confirmed by fluorescent-antibody staining
with a C. pneumoniae-specific monoclonal antibody
(Washington Research Foundation). Patient isolates were passaged five
to six time in cell culture in antibiotic-free medium.
Susceptibility testing of
C. pneumoniae was performed in
cell culture by using HEp-2 cells grown in 96-well microtiter plates
(
6). Each well was inoculated with 0.2 ml of the organism
diluted
to yield 10
3 inclusion-forming units per ml, and
the plates were centrifuged
at 2,000 ×
g for 1 h.
The wells were then aspirated and overlaid
with 0.2 ml of medium
containing 1 µg of cycloheximide per ml
and serial twofold dilutions
of the test drug. After incubation
at 35°C for 72 h, cultures
were fixed and stained for inclusions
with fluorescein-conjugated
antibody to the lipopolysaccharide
antigen common to
Chlamydia (Pathfinder Chlamydia Culture Confirmation
System;
Kallestad Diagnostics). The MIC was the lowest antibiotic
concentration at which no inclusions were seen. The minimal
chlamydiacidal
concentration (MCC) was determined by freezing the
cultures at
70°C, thawing the cultures, passaging the disrupted
cell monolayers
onto new cells, incubating the cells for 72 h, and
then fixing
and staining the cells as described above. The MCC was the
lowest
antibiotic concentration which resulted in no inclusions after
passage. All tests were run in triplicate.
C. pneumoniae was isolated from 10 of 48 (20.8%) patients
with pneumonia who were enrolled in the adult study. Patients were
from
six sites in five states (Georgia, New York, Wisconsin, Texas,
and
Massachusetts) and the District of Columbia.
C. pneumoniae was eradicated from the nasopharynges of 7 of the 10 (70%)
culture-positive
pneumonia patients after treatment. We were able to
retrieve five
additional isolates from the three persistently infected
patients.
The MIC at which 50% of the isolates were inhibited
(MIC
50) and
MIC
90 for these 15 isolates were
both 0.25 µg/ml (range, 0.015
to 0.25 µg/ml). The
MCC
90s were 0.25 µg/ml (range, 0.015 to 0.25
µg/ml).
The in vitro susceptibilities of the isolates from the
three
persistently infected patients are shown in Table
1. The
MICs did not change during or
after therapy except for patient
072. Both the MICs and MCCs for two
isolates obtained from this
patient after treatment increased fourfold,
from 0.062 to 0.25
µg/ml. Despite persistence of
C. pneumoniae, all patients improved
clinically.
View this table:
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TABLE 1.
In vitro susceptibilities to azithromycin of isolates
of C. pneumoniae from three persistently positive
adults with pneumonia
|
|
A total of 456 children with pneumonia from 27 sites in 20 states were
enrolled in the pediatric treatment study.
C. pneumoniae was
isolated from 36 (7.9%) of the children. Two culture-positive
patients
did not return for any follow-up visits, leaving 34 patients
for whom
we could evaluate microbiologic efficacy.
C. pneumoniae was
eradicated after treatment from the nasopharynges of 19 of
23 (83%)
evaluable patients who received azithromycin and 4 of
4 and 7 of 7 of
those patients who received amoxicillin-clavulanate
and erythromycin,
respectively (
P = 0.9, chi-square test).
MICs and MCCs of azithromycin and erythromycin for 40 isolates of
C. pneumoniae from 36 pediatric patients were determined.
The MIC
50 and MIC
90 of azithromycin were 0.125 and 0.5 µg/ml (range,
0.015 to 0.5 µg/ml), respectively. The
MIC
50 and MIC
90 of erythromycin
were 0.062 and
0.25 µg/ml (range, 0.015 to 0.5 µg/ml), respectively.
As shown in
Table
2, the MICs and MCCs for the
isolates from
one of four persistently infected children (patient 015)
increased
fourfold, from 0.031 to 0.125 µg/ml for both azithromycin
and
erythromycin.
View this table:
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[in a new window]
|
TABLE 2.
MICs and MCCs for isolates of C. pneumoniae
from four persistently positive children with pneumonia treated
with azithromycina
|
|
The efficacies of azithromycin for eradication of
C. pneumoniae from the nasopharynges of adults and children with
pneumonia
were 70% (7 of 10) and 83% (19 of 23), respectively.
Overall,
C. pneumoniae was eradicated from the nasopharynges
of 26 of the
33 (78.8%) patients who were treated with azithromycin.
The numbers
of children treated with the drugs used for comparison were
too
small to make any meaningful comparisons. Persistence did not
appear to be related to poor compliance by the adults or the children.
The parents brought back the bottles of suspension, which were
weighed,
and the amount of drug actually given was calculated.
These results are
comparable to those of our previous study of
the treatment of
C. pneumoniae pneumonia in children, in which
we found a
microbiologic efficacy of 79% (15 of 19) for clarithromycin
and 86%
(12 of 14) for erythromycin (
2). There are no published
data
on the microbiological efficacy of azithromycin for treatment
of
C. pneumoniae infections in adults.
Few published data on the efficacy of any treatment regimen for
eliminating
C. pneumoniae from the respiratory tract exist.
We have observed several patients who have remained persistently
culture positive and clinically symptomatic despite 7- to 30-day
courses of doxycycline, tetracycline, and erythromycin (
5).
There are no published pneumonia treatment studies that have assessed
the efficacy of azithromycin for the treatment of
C. pneumoniae infection by utilizing culture (
11-13). All
have relied on serology
for diagnosis, which has a very poor
correlation with culture
positivity, especially in children
(
2). A recent study of children
compared the efficacy of a
3-day course of azithromycin to 10
days of erythromycin for the
treatment of community-acquired pneumonia
(
11). Although it
was stated in that study that serology for
C. pneumoniae was
determined by the microimmunofluorescence method,
no data on the number
of children who had serologic evidence of
infection were presented,
which suggests that perhaps none were
positive. Block et al. found that
77% of the children in their
study with culture-positive
C. pneumoniae pneumonia were antibody
negative by
microimmunofluorescence (
2).
The MICs and MCCs of azithromycin for the strains isolated from the
patients in these two studies were similar to what we
have previously
reported (
6). There was no difference in susceptibility
between the strains isolated from adults and children. We previously
reported the MIC
90 and MCC
90 of azithromycin to
be 0.125 and 0.25
µg/ml, respectively (
6). Only 11 strains, primarily from adults
from Brooklyn, N.Y., were tested in that
study. None of those
patients were treated with azithromycin. The data
presented here
are the result of the first attempt to correlate the
results of
treatment with azithromycin and in vitro susceptibility with
a
large number of strains from diverse geographical areas. The MICs
and
MCCs for three of nine isolates obtained after treatment from
two of
seven persistently infected patients who were treated with
azithromycin
increased fourfold after treatment, although they
were still within the
range considered to indicate susceptibility
to the antibiotic. It is
not clear if this is an isolated event
or suggestive of possible
development of resistance. All patients
improved clinically despite
persistence of the organism. In our
previous experience with the use of
clarithromycin and erythromycin
we did not find any change in MIC or
MCC despite persistence of
the organism in eight children with
pneumonia, two of whom were
treated with erythromycin and six of whom
were treated with clarithromycin
(
10). The results of in
vitro susceptibility testing may not
always predict in vivo efficacy.
Although relative resistance
of
Chlamydia trachomatis to
erythromycin and doxycycline has been
reported, the relationship to
treatment failure is unclear (
7,
8). Further studies of
treatment of
C. pneumoniae infection,
utilizing
culture, are needed both to assess efficacy and to monitor
for the
possible development of antibiotic resistance.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Pediatrics, Box 49, SUNY Health Science Center at Brooklyn, 450 Clarkson Ave., Brooklyn, NY 11203-2098. Phone: (718) 245-4075. Fax:
(718) 245-2118. E-mail: mhammerschlag{at}pol.net.
| |
REFERENCES |
| 1.
| Anderson, G., T. S. Esmonde, S. Coles, J. Macklin, and C. Carnegie. 1991. A comparative study of
clarithromycin and erythromycin stearate in community acquired
pneumonia. J. Antimicrob. Chemother. 27(Suppl.
A):117-124.
|
| 2.
|
Block, S.,
J. Hedrick,
M. R. Hammerschlag,
G. H. Cassell, and C. Craft.
1995.
Mycoplasma pneumoniae and Chlamydia pneumoniae in pediatric community-acquired pneumonia: comparative efficacy and safety of clarithromycin vs erythromycin ethylsuccinate.
Pediatr. Infect. Dis. J.
14:471-477[Medline].
|
| 3.
|
Chien, S. M.,
P. Pichotta,
N. Stepman, and C. K. Chan.
1993.
Treatment of community-acquired pneumonia. A multicenter, double blind, randomized study comparing clarithromycin to erythromycin.
Chest
103:697-701[Abstract/Free Full Text].
|
| 4.
|
Grayston, J. T.,
L. A. Campbell,
C.-C. Kuo,
C. H. Mordhorst,
P. Saikku,
D. H. Thom, and S. P. Wang.
1990.
A new respiratory tract pathogen: Chlamydia pneumoniae strain TWAR.
J. Infect. Dis.
161:618-625[Medline].
|
| 5.
|
Hammerschlag, M. R.,
K. Chirgwin,
P. M. Roblin,
M. Gelling,
W. Dumornay,
L. Mandel,
P. Smith, and J. Schachter.
1992.
Persistent infection with Chlamydia pneumoniae following acute respiratory illness.
Clin. Infect. Dis.
14:178-182[Medline].
|
| 6.
|
Hammerschlag, M. R.,
K. K. Qumei, and P. M. Roblin.
1992.
In vitro activities of azithromycin, clarithromycin, L-ofloxacin, and other antibiotics against Chlamydia pneumoniae.
Antimicrob. Agents. Chemother.
36:1573-1574[Abstract/Free Full Text].
|
| 7.
|
Jones, R. B.,
B. Van Der Pol,
D. H. Martin, and M. K. Shepard.
1990.
Partial characterization of Chlamydia trachomatis isolates resistant to multiple antibiotics.
J. Infect. Dis.
162:1309-1315[Medline].
|
| 8.
|
Mourad, A.,
R. L. Sweet,
N. Sugg, and J. Schachter.
1980.
Relative resistance to erythromycin in Chlamydia trachomatis.
Antimicrob. Agents Chemother.
18:696-698[Abstract/Free Full Text].
|
| 9.
|
Roblin, P. M.,
W. Dumornay, and M. R. Hammerschlag.
1992.
Use of HEp-2 cells for improved isolation and passage of Chlamydia pneumoniae.
J. Clin. Microbiol.
30:1968-1971[Abstract/Free Full Text].
|
| 10.
|
Roblin, P. M.,
G. Montalban, and M. R. Hammerschlag.
1994.
Susceptibilities to clarithromycin and erythromycin of isolates of Chlamydia pneumoniae from children with pneumonia.
Antimicrob. Agents Chemother.
38:1588-1589[Abstract/Free Full Text].
|
| 11.
|
Roord, J. J.,
B. H. M. Wolf,
M. M. H. T. Goossens, and J. L. L. Kimpen.
1996.
Prospective open randomized study comparing efficacies and safeties of a 3-day course of azithromycin and a 10-day course of erythromycin in children with community-acquired acute lower respiratory tract infections.
Antimicrob. Agents Chemother.
40:2765-2768[Abstract].
|
| 12.
|
Schoenwald, S.,
V. Skerk,
I. Petricevec,
V. Car,
L. Majerus-Misic, and M. Gunjaca.
1991.
Comparison of three-day and five-day courses of azithromycin in the treatment of atypical pneumonia.
Eur. J. Clin. Microbiol. Infect. Dis.
10:877-880[Medline].
|
| 13.
|
Schonwald, S.,
B. Barsic,
I. Klinar, and M. Gunjaca.
1994.
Three-day azithromycin compared with ten-day roxithromycin treatment of atypical pneumonia.
Scand. J. Infect. Dis.
26:706-710[Medline].
|
Antimicrobial Agents and Chemotherapy, January 1998, p. 194-196, Vol. 42, No. 1
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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