BREAKPOINTS: A SHORT HISTORY AND OVERVIEW

3. BREAKPOINTS: A SHORT HISTORY AND OVERVIEW

The criteria used for categorization in “susceptible” and “resistant,” and the meaning of S and R, have varied over time and place and are not always clear. Initially, the terms susceptible and resistant were largely based on frequency distributions, the distributions of the populations being well apart and largely confined to distinguishing susceptible from resistant Staphylococcus aureus strains, which correlated well with clinical success and failure. From that per- spective the term breakpoint was first used in the Report of an International Collaborative Study on Antimicrobial Susceptibility Testing by Ericsson and Sherris in 1971 (Ericsson and Sherris, 1971). Since then, interpretation and use have diverged between various countries, persons and societies, with major differences in approach between Europe and the United States. This has led to breakpoint values diverging by as much as a factor 32 for some drugs. In Europe, most of the national breakpoint committees were, apart from creating reproducible antimicrobial susceptibility testing (AST) methods, primarily interested in providing breakpoints which could be used to predict clinical and bacteriological efficacy based on serum concentrations achieved in patients. In most cases, the duration of time that the free fraction remained above a certain value was considered to be the breakpoint and less attention was paid, except for notably the SRGA in Sweden and the BSAC in the United Kingdom, to the fact that the natural population distribution of MICs could be divided by using this approach too rigorously. Alternatively, the line in the United States tended to categorize bacteria based on frequency distributions and thus in some cases breakpoints that were higher than the highest concentration were achieved clinically. Table 1 shows an overview of the various approaches used in six European countries and the United States.

It was mentioned above that in particular the SRGA and the BSAC took the population distribution into account when setting their breakpoints. The reason for this was that the reproducibility and accuracy of MIC testing (or measuring zone diameters) in the routine medical microbiology laboratory does not allow a precise answer: In general, the accuracy of MIC measurement is within 1–2 twofold dilutions, while the wild-type population distribution spans a concentra- tion range of 3–4 twofold dilutions. Thus, it is impossible to determine the exact MIC from a single measurement and whether a particular strain belongs to the upper part or the lower part of the population distribution. Indeed, the distribu- tion of measurements of the same strain is very similar to that of the distribution

396 Johan W. Mouton

Table 1. Breakpoint systems used Country

References France

Formula a based on PK ⫽

(Soussy et al., 1994) (C max /3 ⫹ Ct – 1 2 ⫹ C4h)/3 ⫻ (1 ⫺ k)

Great BSAC Formula b based on PK ⫽ C max ⫻ (MacGowan and Britain

Wise, 2001) Netherlands

f ⫻ s/(e ⫻ t)

CRG

70–80% T ⬎MIC for non-protein

(Mouton et al., 2000)

bound fraction

Sweden SRGA

Pharmacokinetic profile and

(Swedish Reference

frequency distribution,

Group of Antibiotics,

1997) Norway

species dependent

(Bergan et al., 1997) Germany

NWGA

67% T ⬎MIC

DIN

Pharmacokinetic profile,

(Deutsches Institut

fur Normung, 1990) Europe

frequency distributions, efficacy

EUCAST

Clinical breakpoints: PK profile

(EUCAST, 2003)

and efficacy Wild-type cut-offs: frequency distribution

US NCCLS Frequency distribution, pharmaco- (NCCLS, 2002,

kinetic profile

2 , concentration in serum after one half-life; C4h, minimum quantity obtained over 4 hr period that corresponds approximately to 10 bacterial

a C max , maximum serum concentration; Ct 1 –

generations; k, degree of protein binding. b C max , maximum serum concentration at steady state, usually 1 h post-dose; e, factor by

which C max should exceed MIC (usually 4); t, factor to allow for serum half-life; f, factor to allow for protein binding; s, shift factor to allow for reproducibility and frequency distributions (usually 1).

of strains within a species (Figure 6). Consequently, the MIC or zone diameter to indicate whether a strain is susceptible or resistant, the breakpoint, has be either at the lower or at the upper end of the distribution but not in the middle.

3.1. Different breakpoints, different resistance rates

Since there are different breakpoints in use for some (most) drugs in vari- ous countries, it is obvious that the resistance rates in these countries differ, if only because of the definition used. It is therefore not very rational to compare resistance rates between countries if the breakpoints countries use differ and it is not known what the effect of these different breakpoints is on the resistance rates. An example of the various rates one might obtain using breakpoints from different countries is shown in Figure 7 for cefotaxime and Escherichia coli.

Impact of Pharmacodynamics on Dosing Schedules 397

Figure 6. Distributions of zone diameters from repeated measurements of the quality control strain (left) and clinical isolates from the same species (right). The distributions are rela- tively similar, except for the resistant strains, which is particularly obvious for tetracycline. Reproduced from Mouton, 2002.

MIC mg/L

Figure 7. Distribution of cefotaxime MICs of E. coli. Based on data from de Man et al., 1998.

The susceptibility data were taken from a survey of urinary isolates in the Netherlands (de Man et al., 1998). Table 2 lists the current breakpoints for cefotaxime as used by various breakpoint committees (Kahlmeter et al., 2003). Depending on the breakpoint used, the resistance rates range from 0.5% to 4%. For other drugs, the differences may be much larger.

398 Johan W. Mouton

Table 2. Similarities and differences in international breakpoint systems—current cefotaxime and ciprofloxacin breakpoints for Enterobacteriaceae in Europe and the United States. Reproduced from (Kahlmeter et al., 2003)

Breakpoint

Ciprofloxacin committee (country)

Cefotaxime breakpoint

breakpoint (mg/L) Susceptible

(mg/L)

Susceptible Resistant BSAC (UK)

Resistant

2 4 1 2 CA-SFM (France)

1 ⬎2 CRG (Netherlands)

1 ⬎2 DIN (Germany)

2 16 1 4 NCCLS (USA)

8 64 1 4 NWGA (Norway

1 32 0.12 4 SRGA (Sweden)

3.2. Breakpoint harmonization in Europe

It is apparent that the difference in breakpoints within Europe leads to confusion and may lead to erroneous conclusions. Given the similarities in dosing within the various countries in Europe, it seems logical that breakpoints within Europe should be harmonized. The discussion above has also shown two important fundamentals in setting breakpoints that were not clearly distin- guished or recognized in the past. The first is that, over the last decade, clear dose–effect relationships have been established for antimicrobials and microorganisms and that these relationships can be used to set breakpoints to help guide therapy. At the same time it is recognized that early detection of emergence of resistance is increasingly important, but that clinical breakpoints are not particularly suitable to detect that. The EUCAST has therefore con- cluded that these two objectives of using breakpoints serve different purposes and that therefore, apart from clinical breakpoints, a new type of breakpoints should be introduced (EUCAST, 2003). These are wild-type cut-off values and are set at the edge of the wild-type distribution. Microorganisms that have MICs higher than this value will be easily detected, even if the MICs are well below the clinical breakpoint. For instance, in a study by Grohs et al. (2003), the wild-type MIC for moxifloxacin is 0.125 mg/L while strains with single ParC mutations have MICs of 0.5 mg/L. Since the clinical break- point of moxifloxacin is above 0.5 mg/L, these strains, indicating emergence of resistance, would not be identified using clinical breakpoints. A wild-type cut- off value of 0.25 mg/L however would pick-up these strains, alert the labora- tory that this strain is not wild-type and subsequently relevant action can be taken.

Impact of Pharmacodynamics on Dosing Schedules 399

3.3. Use of PK/PD to set clinical breakpoints for quinolones

Based on PK/PD relationships, considering that the dosing regimens in vari- ous countries in Europe are largely similar, EUCAST has proposed clinical breakpoints for a variety of antimicrobials and is still in the process of complet- ing those for all antimicrobials. The breakpoints for quinolones are shown in Table 4 and are based on the pharmacokinetic properties of the drug (Table 3; EUCAST, 2003). The breakpoint values are consistent in that the S breakpoint determined from the AUC/MIC ratio is similar for all quinolones. There is one notable exception, the S breakpoint for levofloxacin and S. pneumoniae. The S breakpoint here is 2 mg/L instead of 1 mg/L because a 1 mg/L breakpoint would divide the wild-type population. It has to be realized however that the downside of designating all S. pneumoniae strains with an MIC of ⱕ2 mg/L susceptible is, that the probability of a successful outcome is slightly less than one would conventionally presume. This may be overcome by using a higher dose.

From the discussions above it thus becomes apparent and evident that two different types of breakpoints are required. Clinical breakpoints based on PK/PD relationships confer a different meaning to resistance than early detec- tion of microorganisms that do not belong to the natural bacterial population, but somehow have acquired resistance mechanisms. An example is shown in Figure 8 for ciprofloxacin and E. coli. The figure shows the MIC distributions of E. coli from a variety of sources (EUCAST, 2003) with arrows indicating the wild-type cut-off breakpoint (for epidemiological purposes and early detec- tion of emergence of resistance) as well as clinical breakpoints (based on PK/ PD and probability of cure).

It has to be emphasized that clinical breakpoints may vary over time and place because they are dose dependent, but that wild-type cut-off values do not, because the susceptibility of wild-type bacteria to a drug is a universal charac- teristic. It is thus that the wild-type cut-off is especially suited to compare rates of resistance between countries and over time.

Table 3. PK parameters of four fluoroquinolones based on dosing regimens generally used. Adapted from Mouton, 2002

Fluoro Regimen

AUC Protein quinolone

C max

(mg/L)

(mg • hr/L) binding (%)

Ciprofloxacin 500 mg/12 hr 2.8 22.2 22 Levofloxacin

500 mg/24 hr 5.2 61.1 30 Ofloxacin

200 mg/12 hr 2.2 29.2 30 Moxifloxacin

400 mg/24 hr 4.5 48.0 40

Table 4. EUCAST breakpoints for quinolones (EUCAST, 2003) Fluoro

Non- quinolone a

Species-related breakpoints (S ⱕ / R⬎)

species Entero bacteriaceae b

Pseudo- Acineto- Staphylo- Entero-

Strepto-

S. pneu- d H. influenzae e N. gonorr- N. menin- Anaerobe related

monas

bacter

coccus c

M. catarrhalis

hoeae

gitidis f bactera breakpoints 8

Sⱕ/R⬎ Ciprofloxacin

A,B,C,G

IE IE — 1/2 Moxifloxacin

IE IE IE 1/2 Ofloxacin

IE — 0.5/1 Notes: ‘—’ ⫽ Susceptibility testing not recommended as the species is a poor target for therapy with the drug.

IE ⫽ There is insufficient evidence that the species in question is a good target for therapy with the drug. a For breakpoints for other fluoroquinolones (e.g., pefloxacin and enoxacin)—refer to breakpoints determined by national breakpoint committees.

b Salmonella spp.—there is clinical evidence for ciprofloxacin to indicate a poor response in systemic infections caused by Salmonella spp. with low-level fluoroquinolone resistance (MIC ⬎ 0.064 mg/L).

c Staphylococcus spp.—breakpoints for ciprofloxacin and ofloxacin relate to high dose therapy. d Streptococcus pneumoniae—wild-type S. pneumoniae are not considered susceptible to ciprofloxacin or ofloxacin and are therefore categorized as intermediate. For

ofloxacin the I/R breakpoint was increased from 1.0 to 4.0 mg/L to avoid dividing the wild-type MIC distribution. The breakpoints for levofloxacin relate to high dose therapy.

e Haemophilus/Moraxella—fluoroquinolone low-level resistance (ciproflocacin MICs of 0.125–0.5 mg/L) may occur in H. influenzae. There is no evidence that low- level resistance is of clinical importance in respiratory tract infections with H. influenzae. An intermediate category was not defined since only few clinically resistant

strains have been reported. f

Johan W

Neisseria meningitidis—breakpoints apply to the use of ciprofloxacin in the prophylaxis of meningococcal disease. g Non-species related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for

use only for species that have not been given a species-specific breakpoint and not for those species where susceptibility testing is not recommended (marked with “—” or IE in the table).

Mouton .

Impact of Pharmacodynamics on Dosing Schedules 401

Figure 8. Distribution of E. coli MICs of ciprofloxacin from various sources (EUCAST, 2003). Arrows indicate the wild-type cut-off and clinical breakpoints, respectively.