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editorial
. 2000 Nov;44(11):3243–3245. doi: 10.1128/aac.44.11.3243-3245.2000

Assumed versus Approved Breakpoints

David A Preston 1, Mark R Turnak 1
PMCID: PMC101647  PMID: 11184232

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.

REFERENCES

  • 1.Jacobs M R, Bajaksouzian S, Zilles A, Lin G, Pankuch G A, Appelbaum P C. Susceptibilities of Streptococcus pneumoniae and Haemophilus influenzaeto 10 oral antimicrobial agents based on pharmacodynamic parameters: 1997 U.S. surveillance study. Antimicrob Agents Chemother. 1999;43:1901–1908. doi: 10.1128/aac.43.8.1901. [DOI] [PMC free article] [PubMed] [Google Scholar]
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  • 4.Zhanel G G, Karlowsky J A, Palatnick L, Vercaigne L, Low D E, Hoban D J The Canadian Respiratory Infection Study Group. Prevalence of antimicrobial resistance in respiratory tract isolates of Streptococcus pneumoniae: results of a Canadian national surveillance study. Antimicrob Agents Chemother. 1999;43:2504–2509. doi: 10.1128/aac.43.10.2504. [DOI] [PMC free article] [PubMed] [Google Scholar]
Antimicrob Agents Chemother. 2000 Nov;44(11):3243–3245.

AUTHORS' REPLY

Michael R Jacobs 1,2,3,4, Peter C Appelbaum 1,2,3,4, George G Zhanel 1,2,3,4, Donald E Low 1,2,3,4

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 (1-7), and the dynamics of this relationship was first demonstrated in animal models by Vogelman et al. in 1988 (1-15). 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 (1-1–1-4, 1-9). 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 (1-5). 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 (1-10). Additionally, pharmacodynamic breakpoints have recently been used to develop new guidelines for the treatment of otitis media (1-6) and sinusitis (1-14). 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 (1-1–1-4). 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. (1-5), 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. (1-10). 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 (1-11).

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 (1-9, 1-13). 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% (1-8). 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 (1-3, 1-4). 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 (1-8, 1-9). 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 (1-12), 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.

REFERENCES

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Antimicrob Agents Chemother. 2000 Nov;44(11):3245.

EDITORIAL COMMENT

William Craig 1

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 (2-1, 2-2). 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

  • 2-1.Hanberger H, Nilsson L E, Calesson B, Karnell A, Larsson P, Rylander M, Svensson E, Sorber M, Soren L. New species-related MIC breakpoints for early detection of development of resistance among Gram-negative bacteria in Swedish intensive care units. J Antimicrob Chemother. 1999;44:611–619. doi: 10.1093/jac/44.5.611. [DOI] [PubMed] [Google Scholar]
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