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Antimicrobial Agents and Chemotherapy, November 2000, p. 3243-3245, Vol. 44, No. 11
0066-4804/00/$04.00+0
LETTERS TO THE EDITOR
Assumed versus Approved Breakpoints
 |
LETTER |
In our opinion, recent articles by Jacobs et al. (1)
and Zhanel et al. (4) disseminated misleading information.
Our first objection is that the authors failed to abide by the
journal's policy of not assigning interpretive MIC breakpoints in the
absence of approved breakpoints. The Instructions to Authors are
explicit on this point:
"The percentage of strains susceptible and/or resistant to an
antibiotic at its breakpoint concentration may be given only if an
appropriate breakpoint has been approved, as by the National Committee
for Clinical Laboratory Standards, 940 W. Valley Rd., Suite 1400, Wayne, PA 19087-1898. In the absence of approved breakpoints, authors
cannot assign breakpoints, use breakpoints from related antibiotics, or
use a range of concentrations to report a cumulative display of percent
susceptible/resistant strains."
Jacobs et al. and Zhanel et al. reported percent susceptibility of
Streptococcus pneumoniae to cefaclor using assumed
breakpoints. Zhanel et al. assumed breakpoints that are approved for
cefuroxime, and Jacobs et al. used breakpoints derived by application
of pharmacodynamic (PD) principles. The use of an assigned breakpoint
for susceptibility (
0.5 µg/ml) resulted in fewer than a quarter and
just over half of the penicillin-susceptible S. pneumoniae
(PSSP) strains being classified as susceptible to cefaclor,
respectively, in the two papers. Those findings are inconsistent with
long-standing clinical experience and with NCCLS recommendations. Since
its registration, cefaclor has proven itself, time and time again,
effective in treatment of infections caused by PSSP. Since the early
1990s, NCCLS has recommended reporting all PSSP strains as susceptible to cefaclor (2). That recommendation remains in the most
recent iteration of NCCLS interpretive standards (3), which
also includes the recently adopted cefaclor-specific pneumococcal MIC
breakpoint for susceptibility, 1 µg/ml.
Our second objection concerns the lack of attention to detail that
Jacobs et al. used in abstracting their manuscript. Within the body of
the article, they compared their PD breakpoint with the NCCLS
established breakpoint for Haemophilus influenzae. Even though there is considerable explanation of this comparison within the
text, this information was not included in the abstract. Unfortunately, the abstract includes only the susceptibility rate (2%) derived using
the PD breakpoint, without mentioning the result determined using the
NCCLS breakpoint (79%). It is well accepted that the majority of
individuals screening articles, through either literature searches or
personal reading, review only the abstracts of published manuscripts.
Therefore, neglecting to include the percent susceptible by the NCCLS
breakpoint only serves to allow the casual reader to misinterpret the
published work.
We are troubled by these irregularities since they represent both a
disregard for your journal's Instructions to Authors and a breakdown
in the refereeing process that was designed to ensure the scientific
rigor of the journal. Occurrences such as these only serve to misinform
the reader and to tarnish the reputation of this journal in the eyes of
the scientific community.
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REFERENCES |
| 1.
|
Jacobs, M. R.,
S. Bajaksouzian,
A. Zilles,
G. Lin,
G. A. Pankuch, and P. C. Appelbaum.
1999.
Susceptibilities of Streptococcus pneumoniae and Haemophilus influenzae to 10 oral antimicrobial agents based on pharmacodynamic parameters: 1997 U.S. surveillance study.
Antimicrob. Agents Chemother.
43:1901-1908[Abstract/Free Full Text].
|
| 2.
|
National Committee for Clinical Laboratory Standards.
1997.
Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, 4th ed. Approved standard M7-A4
National Committee for Clinical Laboratory Standards, Wayne, Pa.
|
| 3.
|
National Committee for Clinical Laboratory Standards.
2000.
Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, 5th ed. Approved standard
National Committee for Clinical Laboratory Standards, Wayne, Pa.
|
| 4.
|
Zhanel, G. G.,
J. A. Karlowsky,
L. Palatnick,
L. Vercaigne,
D. E. Low,
The Canadian Respiratory Infection Study Group, and D. J. Hoban.
1999.
Prevalence of antimicrobial resistance in respiratory tract isolates of Streptococcus pneumoniae: results of a Canadian national surveillance study.
Antimicrob. Agents Chemother.
43:2504-2509[Abstract/Free Full Text].
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| | | | |
David A. Preston
Mark R. Turnak
Eli Lilly and Company
Indianapolis, Indiana
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| |
AUTHORS' REPLY |
Our first responsibility as physicians and scientists in publishing in
vitro susceptibility data is patient welfare. Results must be
clinically relevant, based on and predictive of patient outcome, and
applicable to patient management. The fact that the concentration of an
antimicrobial agent had to exceed the in vitro inhibitory or lethal
concentration of the agent to be effective was first documented by
Eagle and colleagues almost 50 years ago (7), and the
dynamics of this relationship was first demonstrated in animal models
by Vogelman et al. in 1988 (15). It has come to the
attention of many workers in the field of oral antimicrobial agents and
bacterial respiratory tract infections that many of the breakpoints
used to classify the susceptibilities of S. pneumoniae and
H. influenzae to oral agents do not correspond with clinical and bacteriological outcomes of infections such as otitis media, sinusitis, and acute exacerbations of chronic bronchitis (1-4, 9). Many of these breakpoints are actually higher than peak concentrations of the agents in serum and tissue, so that clinically achievable concentrations can never reach, let alone exceed, the concentrations needed to inhibit organisms for which the MICs are at or
close to the susceptibility breakpoint values.
To specifically address the points made by Preston and Turnak, firstly
the fact that Antimicrobial Agents and Chemotherapy published our papers speaks to the validity of our argument that many
current breakpoints need to be revised. Nevertheless, all available
NCCLS breakpoints at the time the manuscripts were submitted were used.
However, many of the breakpoints had been set some time ago, and, due
to the nature of the process required to modify them, may not be
current. Antimicrobial Agents and Chemotherapy is not the
only reputable peer-reviewed journal recently allowing use of
alternative breakpoints under these circumstances. Doern et al. used an
S. pneumoniae susceptibility breakpoint of 0.5 µg/ml for
cefadroxil, cefaclor, cefixime, and cefpodoxime in a paper published in
1998 in Clinical Infectious Diseases (5). Pharmacodynamic breakpoints were also used by Mason et al. in a study
just published in the Journal of Antimicrobial Chemotherapy reporting in vitro susceptibility and pharmacodynamic analysis of
S. pneumoniae in the United States (10).
Additionally, pharmacodynamic breakpoints have recently been used to
develop new guidelines for the treatment of otitis media (6)
and sinusitis (14). We also point out that, at the time of
submission of our manuscripts, the new NCCLS breakpoints for S. pneumoniae had not been finalized, and we were not allowed to use
or even mention the new or proposed breakpoints until they were
published (in January 2000).
Secondly, the use of 0.5 µg/ml as the breakpoint for cefaclor in
the paper by Jacobs et al. was based on clinical and pharmacodynamic correlations, which repeatedly showed this value to be the
susceptibility breakpoint (1-4). In the paper by Jacobs et
al. the percentage of penicillin-susceptible isolates of S. pneumoniae that are susceptible to cefaclor is 43.7%, not
"fewer than a quarter" of isolates. Interestingly, very similar
values, 51 and 46.6%, were obtained by Zhanel et al. and Doern et al.
(5), while the MIC of cefaclor was 0.5 µg/ml for only
16.7% of penicillin-susceptible isolates in the study by Mason et al.
(10). Based on available clinical studies using
bacteriologic eradication during therapy and clinical outcome at end of
therapy as parameters, we believe that 0.5 µg/ml is the appropriate
breakpoint for current dosing regimens of cefaclor for S. pneumoniae, H. influenzae, and possibly other extracellular respiratory tract pathogens. New cefaclor formulations and dosing regimens (500-mg regular formulation three times a day and
750-mg extended-release formulation twice a day) have been shown to
have improved pharmacokinetic profiles, with serum drug concentrations
of 0.5 and 1 µg/ml being exceeded for 50 and 40% of the dosing
interval, respectively (11).
Thirdly, Preston and Turnak assert that cefaclor is effective in
treatment of infections caused by penicillin-susceptible S. pneumoniae based on long-standing clinical experience and NCCLS recommendations. This statement is not substantiated by any
peer-reviewed papers. Many authors have questioned this "conventional
wisdom" approach to medicine, and recommend that decisions be made on the basis of sound scientific evidence using adequately designed studies (9, 13). In a 1993 review, Klein summarized
bacteriologic outcomes reported in acute otitis media studies and noted
that the bacteriologic failure rate of cefaclor in S. pneumoniae infections varied from 2.7 to 52.9%, with an overall
failure rate of 18.2% (8). Comparable values for H. influenzae ranged from 15 to 44.4% (32.9% overall). Two recent
studies by Dagan's group reported bacteriologic failure rates of 0 and
21% against S. pneumoniae isolates for which the MICs of
cefaclor were 0.5 µg/ml, compared to 68 and 57% against isolates
for which the MICs of cefaclor were >0.5 µg/ml (3, 4).
Most of the isolates for which the MICs of cefaclor were 0.5 µg/ml
were penicillin susceptible. Bacteriologic failure rates for patients
with H. influenzae infections in these studies were 38.9 and
55.2%, which are similar to results expected with a placebo (8,
9). Based on these data, the susceptibility breakpoint for
cefaclor appears to be between 0.5 µg/ml (the MICs for isolates
from patients with good response to cefaclor therapy) and >0.5 µg/ml
(the MICs for penicillin-nonsusceptible S. pneumoniae and
for H. influenzae). As the MIC was 1 µg/ml for very few
strains, it is possible that those strains could be susceptible. In the
absence of data at 1 µg/ml, a susceptibility breakpoint of 0.5
µg/ml is supported by the available evidence, and we therefore used
this value. We will be pleased to use a higher breakpoint should data
supporting this become available. However, a breakpoint of 1 µg/ml
still means that the vast majority of penicillin-susceptible S. pneumoniae strains will have marginal MICs (i.e., MICs right at,
or 1 dilution below, the breakpoint), while virtually all H. influenzae and Moraxella catarrhalis isolates will
still be resistant. We also note that Preston and Turnak do not appear to be concerned that the current NCCLS susceptibility breakpoint for
S. pneumoniae is 1 µg/ml while that of H. influenzae is 8 µg/ml (12), resulting in most
isolates of H. influenzae being in the susceptible category.
Fourthly, Preston and Turnak complain that Jacobs et al. omitted NCCLS
breakpoints from the abstract. With a limit of 250 words we regret that
we were unable to include every detail of such a large study in the
abstract and object in the strongest terms to Preston and Turnak's
suggestion that the abstract is deliberately misleading in any way.
Finally, we object strongly to Preston and Turnak's statement that our
papers contained "irregularities." We stand behind our work, which
was based on the best evidence available as well as being peer
reviewed, and leave the decision as to which set of breakpoints is
clinically relevant to the judgement of the discerning reader.
| |
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Craig, W. A.
1998.
Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men.
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Craig, W. A., and D. Andes.
1996.
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Dagan, R.,
O. Abramson,
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D. Greenberg,
R. Lang,
S. Goshen,
P. Yagupsky,
A. Leiberman, and D. M. Fliss.
1997.
Bacteriologic response to oral cephalosporins: are established susceptibility breakpoints appropriate in the case of acute otitis media?
J. Infect. Dis.
176:1253-1259[Medline].
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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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Doern, G. V.,
M. A. Pfaller,
K. Kugler,
J. Freeman, and R. N. Jones.
1998.
Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY antimicrobial surveillance program.
Clin. Infect. Dis.
27:764-770[Medline].
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Dowell, S. F.,
J. C. Butler,
G. S. Giebink,
M. R. Jacobs,
D. Jernigan,
D. M. Musher,
A. Rakowsky, and B. Schwartz.
1999.
Acute otitis media: management and surveillance in an era of pneumococcal resistance a report from the Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group.
Pediatr. Infect. Dis. J.
18:1-9[CrossRef][Medline].
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Eagle, H.,
R. Fleischman, and M. Levy.
1953.
Continuous vs. discontinuous therapy with penicillin.
N. Engl. J. Med.
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Klein, J.
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Pediatr. Infect. Dis. J.
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Marchant, C. D.,
S. A. Carlin,
C. E. Johnson, and P. A. Shurin.
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J. Pediatr.
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Mason, E. O., Jr.,
L. B. Lamberth,
N. L. Kershaw,
B. L. Prosser,
A. Zoe, and P. G. Ambrose.
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Streptococcus pneumoniae in the USA: in vitro susceptibility and pharmacodynamic analysis.
J. Antimicrob. Chemother.
45:623-631[Abstract/Free Full Text].
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Mazzei, T.,
A. Novelli,
S. Esposito, and P. Periti.
2000.
New insight into the pharmacokinetics of cefaclor: tissue penetration.
J. Chemother.
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National Committee for Clinical Laboratory Standards.
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MIC testing supplemental tables. M100-S10 (M7).
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Reed, R. C.
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J. Infect.
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Sinus and Allergy Health Partnership.
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Antimicrobial treatment guidelines for acute bacterial rhinosinusitis.
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Vogelman, B.,
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|
| | | | |
Michael R. Jacobs
Case Western Reserve University and
University Hospitals of Cleveland
Cleveland, Ohio 44106
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| | | | |
Peter C. Appelbaum
Hershey Medical Center
Hershey, Pennsylvania 17033
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| | | | |
George G. Zhanel
University of Manitoba
Winnipeg, Canada R3A 1R9
|
| | | | |
Donald E. Low
University of Toronto
Toronto, Canada M5G 1X5
|
| |
EDITORIAL COMMENT |
Interpretive breakpoints for susceptibility testing that are developed
by organizations such as the NCCLS (National Committee for Clinical
Laboratory Standards), BSAC (British Society of Antimicrobial Chemotherapy), DIN (Deutsche Industrie Norm-Medizinsche Mikrobiologie), SFM (Societe Francaisae de Microbiologie), and others are known to vary
for many antimicrobial-organism combinations (1, 2). The
scientific rationales for these differences are often not apparent.
Antimicrobial Agents and Chemotherapy (AAC) is interested in
new scientific approaches for establishing interpretive breakpoints. However, we have given and will continue to give preference to published NCCLS breakpoints and guidelines. Although cefaclor did not
have established interpretive breakpoints for S. pneumoniae when the two articles were published, NCCLS documents did state that
penicillin susceptibility results could be applied to cefaclor for this
organism. The distributions of penicillin-susceptible, -intermediate,
and -resistant organisms were included in both articles. The scientific
basis for any proposed breakpoints in manuscripts submitted to AAC must
be clearly described (e.g., pharmacodynamic, pharmacokinetic, or
species-related criteria, etc.), and the proposed breakpoints must be
compared with published NCCLS interpretive breakpoints and guidelines.
| |
REFERENCES |
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|
Hanberger, H.,
L. E. Nilsson,
B. Calesson,
A. Karnell,
P. Larsson,
M. Rylander,
E. Svensson,
M. Sorber, and L. Soren.
1999.
New species-related MIC breakpoints for early detection of development of resistance among Gram-negative bacteria in Swedish intensive care units.
J. Antimicrob. Chemother.
44:611-619[Abstract/Free Full Text].
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| 2.
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Simpson, I.,
J. Durodie,
S. Knott,
B. Shea,
J. Wilson, and K. Machka.
1998.
Effects of following National Committee for Clinical Laboratory Standards and Deutsche Industrie Norm-Medizinische Mikrobiologie guidelines, country of isolate origin, and site of infection on susceptibility of Escherichia coli to amoxicillin-clavulanate (Augmentin).
J. Clin. Microbiol.
36:1361-1365[Abstract/Free Full Text].
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Antimicrobial Agents and Chemotherapy, November 2000, p. 3243-3245, Vol. 44, No. 11
0066-4804/00/$04.00+0
This article has been cited by other articles:
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Jacobs, M. R., Felmingham, D., Appelbaum, P. C., Gruneberg, R. N., the Alexander Project Group,
(2003). The Alexander Project 1998-2000: susceptibility of pathogens isolated from community-acquired respiratory tract infection to commonly used antimicrobial agents. J Antimicrob Chemother
52: 229-246
[Abstract]
[Full Text]
