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Antimicrobial Agents and Chemotherapy, September 2000, p. 2590-2592, Vol. 44, No. 9
0066-4804/00/$04.00+0
LETTERS TO THE EDITOR
Establishing Criteria for Assessment of Efficacy of
Antimicrobial Agents in Acute Otitis Media
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LETTER |
In a recent article, Dagan et al. (1) report on
the comparative bacteriologic efficacies of oral azithromycin and oral cefaclor in children with acute otitis media. The authors assert that
based on a double-tympanocentesis method of evaluating bacteriologic eradication in otitis media susceptibility breakpoints for antibiotics can be determined and previous clinical efficacy studies are inadequate compared to this method. We would like to point out some of the pitfalls inherent in the bacteriologic eradication trials and the
particular bias introduced into the trial described by Dagan et al.
In order to determine bacteriologic efficacy, the authors use a
methodology first utilized by Howie and Ploussard in 1969 (5). Despite 30 years of experience, the
double-tympanocentesis method has yet to be validated in clinical
trials conducted to the most rigorous scientific standards in which all
possible measures to exclude bias are employed. The diagnosis of acute
otitis media is subjective in nature; therefore, the "gold
standard" methodology for evaluation of anti-infective agents is the
double-blind, double-dummy clinical trial using trained otoscopists.
Open-label or single-blinded studies allow bias to influence both
assessment by the investigator and actions of the patient. For example,
the apparent failure of azithromycin to eradicate Haemophilus
influenzae in the study reported by Dagan et al. may be due to the
timing of the tympanocentesis in relation to the time-dependent
bactericidal activity of the drug. In an open-label study, children on
the shorter azithromycin regimen may return to the physician earlier
compared with children on the 10-day beta-lactam regimen. This was, in
fact, the case (Fig. 1). The median time
to second tympanocentesis was 1 day earlier in the azithromycin arm
compared with the cefaclor arm, and this trend, despite the small
sample size, nearly reached statistical significance. A double-blind,
double-dummy clinical trial design minimizes the potential for bias due
to differences in length of therapy.
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FIG. 1.
Median time to second tympanocentesis. For azithromycin
(AZ) the median was 4 days (range, 3 to 6 days). For cefaclor (CFC) the
median was 5 days (range, 4 to 6 days). P = 0.1044.
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Dagan et al. cite their previous publication (2) as evidence
that their model evaluating early bacteriologic eradication is a valid
surrogate for eventual clinical response. The previous report uses the
same data as the azithromycin-cefaclor study, combined with data from
reportedly a third, randomized, amoxicillin-treated group of patients.
The open-label design and the failure to follow the established
randomization schedule preclude an unbiased assessment of
drug-specific clinical response. Therefore, validation of a model
in a three-arm study that uses the same data to report clinical and
bacteriologic results from only two of the arms is a deviation from
sound clinical-trial conduct and emphasizes how important it is to
adhere to established methods in clinical-trial research in order to
remove bias from scientific inference.
Dagan et al. also fail to provide a sound theoretical explanation for
the observed results. The authors postulate that although azithromycin
is highly concentrated in phagocytic leukocytes it is not available in
the extracellular space to act against extracellular pathogens. This is
inconsistent with previous clinical-trial experience and in vitro data
demonstrating that 93.3% of the intracellular amount of azithromycin
is released within 24 h under resting conditions (4)
and immediately in bacteriologic stimulation (J. M. Hyatt, S. A. Mangione, and J. J. Schentag, Fifth Int. Conf. Macrolides Azalides Streptogramins Ketolides Oxazolidinones, abstr. 3.02, 2000).
It remains to be determined whether the timing of the tympanocentesis,
investigator bias, and other factors can be removed from the evaluation
of these double-tap trials. Given the potential pitfalls inherent in
the methodology used in this study, as well as the lack of clinical
validation, it would be premature to consider changes in susceptibility
breakpoints or clinical-trial design based on these data as the authors
have suggested. The peer review community must ask the difficult
questions that might shed light on why a drug that has performed well
in large, double-blinded clinical trials is perceived to be relatively
inactive in children in a small bacteriologic study fraught with
methodological problems. Until the double-tympanocentesis method is
independently validated, clinical researchers should continue to use
established designs for evaluating antimicrobials in otitis media by
conducting large, double-blinded clinical trials in accordance with
advice from experts in the field and the Food and Drug Administration
(3).
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REFERENCES |
| 1.
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Dagan, R.,
E. Leibovitz,
D. M. Fliss,
A. Leiberman,
M. R. Jacobs,
W. Craig, and P. Yagupsky.
2000.
Bacteriologic efficacies of oral azithromycin and oral cefaclor in treatment of acute otitis media in infants and young children.
Antimicrob. Agents Chemother.
44:43-50[Abstract/Free Full Text].
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| 2.
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Dagan, R.,
E. Leibovitz,
D. M. Fliss,
A. Leiberman,
M. R. Jacobs,
W. Craig, and P. Yagupsky.
1998.
Early eradication of pathogens from middle ear fluid during antibiotic treatment of acute otitis media is associated with improved clinical outcome.
Pediatr. Infect. Dis. J.
17:776-782[CrossRef][Medline].
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| 3.
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Food and Drug Administration.
1998.
Draft guidance for industry. Acute otitis media developing antimicrobial drugs for treatment.
FDA Center for Drug Evaluation and Research, Rockville, Md.
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| 4.
|
Gladue, R. P.,
G. M. Bright,
R. E. Isaacson, and M. F. Newborg.
1989.
In vitro and in vivo uptake of azithromycin (CP-62,993) by phagocytic cells: possible mechanism of delivery and release at sites of infection.
Antimicrob. Agents Chemother.
33:277-282[Abstract/Free Full Text].
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| 5.
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Howie, V. M., and J. H. Ploussard.
1969.
"The in-vivo sensitivity test": bacteriology of middle ear exudate during antimicrobial therapy in otitis media.
Pediatrics
44:940-944[Abstract/Free Full Text].
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William Erhardt
Mary Murphy
Charles Knirsch
Pfizer Pharmaceuticals Group
New York, New York
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AUTHORS' REPLY |
We thank the authors of the letter for their comments. We agree that
"the diagnosis of acute otitis media is subjective." Erhardt et al.
suggest that using a trained otoscopist is best. However, even the best
otoscopist can, at best, provide indirect evidence for the presence of
purulent acute otitis media. In contrast, the tympanocentesis method
used in our study enabled us to enroll only patients with direct proof
of purulent otitis as evidenced by the presence of culture-positive
purulent exudate. This is in fact the gold standard for diagnosis of
acute bacterial otitis media. Similarly, the mandatory second
tympanocentesis on day 4 to 6 (3 to 5 days after initiation of therapy)
not only allowed us to evaluate the pathogen eradication rate but also,
in a direct way, the presence and nature of middle ear fluid. No other
indirect method, such as pneumatic otoscopy, is as accurate.
We also agree that the blinded way to evaluate drug efficacy is the
best one, at least for judging clinical improvement, since the symptoms
of otitis are extremely subjective. For these exact reasons we clearly
stated that "all otologic evaluations were done by an
otolaryngologist who was unaware of the culture results and drug
allocation." In addition, we performed a second comparative study (azithromycin versus amoxicillin-clavulanate) in the
United States, Israel, and the Dominican Republic (3). In
that study, also performed using the double-tympanocentesis method, the
clinical outcome was assessed in such a way that the treatment regimen was blinded not only to the otolaryngologist but to the study physician
as well, thus avoiding the potential biases mentioned by Erhardt et al.
The results showed the same poor bacteriologic outcome in the
azithromycin arm in patients with H. influenzae infections.
Furthermore, we are not aware of any studies that evaluated the
bacteriologic efficacy of azithromycin in otitis media other than the
two studies performed by our group, and therefore the results published
in these studies are unique. However, documentation of the failure of
azithromycin and related agents to eradicate H. influenzae
is not unique, as this has been shown in other diseases. Two
comparative studies looking at both bacteriologic and clinical efficacies in acute exacerbations of chronic bronchitis treated with
either azithromycin or clarithromycin made essentially the same point.
In the first study Beghi et al. (1) compared azithromycin and amoxicillin-clavulanate for bacteriologic and clinical outcomes. The bacteriologic efficacies of azithromycin and
amoxicillin-clavulanate were 70 and 100%, respectively, for
Streptococcus pneumoniae and 50 and 100%, respectively, for
H. influenzae. In the second study Chodosh et al.
(2) compared clarithromycin and ciprofloxacin. The
respective values for S. pneumoniae were 93 and 63%, and
for H. influenzae they were 65 and 100%. The clinical
efficacies in the two studies were 68% for azithromycin versus 97%
for amoxicillin-clavulanate and 75% for clarithromycin versus 89% for ciprofloxacin.
Another important point made by Erhardt et al. concerns the timing of
the second tympanocentesis. One of the main reasons for the importance
of timing is the high spontaneous rate of bacteriologic clearance. In
fact, 52% of H. influenzae organisms were spontaneously eradicated at second tympanocentesis, performed 2 to 7 days after the
first one, without antibiotic treatment (4). Erhardt et al.
point out that a "nearly statistically significant" difference in
the timing of the second tympanocentesis between the cefaclor and the
azithromycin groups was present in our study. In fact, H. influenzae eradication rates on day 4 and day 5 in the
azithromycin group were not significantly different: of the 30 children
positive for H. influenzae at enrollment, the second
tympanocentesis was done on day 4 for 13 children and on day 5 or 6 for
17 children (16 on day 5 and 1 on day 6). The respective bacteriologic
failure rates were 7 of 13 (54%) and 9 of 17 (53%), demonstrating
that there was no difference in bacteriologic outcome between day 3 second tympanocentesis and day 4 second tympanocentesis. Thus, the
theoretical criticism raised by Erhardt et al. was not an issue.
Erhardt et al. raise concerns regarding our 1998 study looking at the
correlation between bacteriologic and clinical outcomes, stating that
it was performed with an "open-label" design. In fact, the
otolaryngologist was blinded to the drug regimen and to the culture
results. Furthermore, the otolaryngologist's evaluation was done on
day 4 or 5, at the time of the second tympanocentesis, when the sample
was sent for culture, thus making it a blinded observation with respect
to the results of the culture, which became known only 1 to 3 days
later. The second point in the same paragraph is absolutely not valid,
since our main comparison was between bacteriologically positive and
bacteriologically negative patients at the time of the second tap.
Our response to the comment regarding the theoretical explanation for
the failure of azithromycin to eradicate pathogens is as follows. Even
if we fail to provide a good theoretical explanation, one cannot deny
the facts that the eradication rates of H. influenzae and
macrolide-resistant S. pneumoniae treated with azithromycin were poor and not different from those expected if a placebo had been
administered in two different studies and in more than one country
(1, 2). Erhardt et al. argue that within 24 h, 93.3% of the intracellular amount of azithromycin is released under resting
conditions. They do not take into account the fact that there is a
continued influx of polymorphonuclear leukocytes (PMNs) to the middle
ear cavity in acute otitis media and the drug can immediately enter
fresh PMNs (this occurs in vivo, when a continuous supply of cells
exists). The in vitro models or even specific animal models may
therefore not be appropriate. We would welcome any alternative theory
that could explain the poor results of azithromycin with
macrolide-resistant S. pneumoniae and with H. influenzae but cannot accept denial of the same finding in two studies.
In the last paragraph, Erhardt et al. summarize the letter and try to
provide guidelines. In light of all of the above, it is clear that this
summary is incorrect and contains several presumptuous statements which
have no factual basis. We still believe in the validity of the peer
review process.
Our last comment is that the study was planned in collaboration with
Pfizer International, Pfizer Inc., and was sponsored and monitored by
them as well. It is only after the unfavorable outcome became obvious,
that the present criticisms were expressed. We find no scientifically
sound reasons in the letter of Erhardt et al. to consider our work
invalid in any way and are confident that our findings will be
validated further if additional studies are undertaken.
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REFERENCES |
| 1.
|
Beghi, G.,
F. Berni,
L. Carratu,
A. Casalini,
G. Consigli,
M. D'Anto,
V. Gioia,
A. Molino,
G. Paizis, and A. Vaghi.
1995.
Efficacy and tolerability of azithromycin versus amoxicillin/clavulanic acid in acute purulent exacerbation of chronic bronchitis.
J. Chemother.
7:146-152[Medline].
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| 2.
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Chodosh, S.,
A. Schreurs,
G. Siami,
H. W. Barkman, Jr.,
A. Anzueto,
M. Shan,
H. Moesker,
T. Stack, and S. Kowalsky.
1998.
Efficacy of oral ciprofloxacin vs. clarithromycin for treatment of acute bacterial exacerbations of chronic bronchitis. The Bronchitis Study Group.
Clin. Infect. Dis.
27:730-738[Medline].
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| 3.
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Dagan, R.,
C. Johnson,
S. McLinn,
N. Abughali,
J. Feris,
E. Leibovitz,
D. J. Burch, and M. R. Jacobs.
2000.
Bacteriologic and clinical efficacy of amoxicillin-clavulanate versus azithromycin in acute otitis media.
Pediatr. Infect. Dis. J.
19:95-104[CrossRef][Medline].
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| 4.
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Howie, V. M., and J. H. Ploussard.
1972.
Efficacy of fixed combination antibiotics versus separate components in otitis media.
Clin. Pediatr.
11:205-214.
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Ron Dagan
Eugene Leibovitz
Pediatric Infectious Disease Unit
Soroka University Medical Center
and
The Ben-Gurion University of the Negev
Beer-Sheva, Israel
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Michael R. Jacobs
Department of Pathology
Case Western Reserve University School of Medicine
University Hospitals of Cleveland
Cleveland, Ohio
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Antimicrobial Agents and Chemotherapy, September 2000, p. 2590-2592, Vol. 44, No. 9
0066-4804/00/$04.00+0
