a Research Area, Fundación Jiménez Díaz, Madrid; b Medical Department, SmithKline Beecham Pharmaceuticals, C/Valle de la Fuenfría no. 3, D-28034 Madrid; c Microbiology Department, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid; d Clinical Microbiology Department, Hospital Ramón y Cajal, Madrid, Spain
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Abstract |
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Introduction |
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The aim of this study was to assess the evolution of Streptococcus pneumoniae resistance to penicillin (with special attention to high-level resistance, which may be likely to preclude antibiotic treatment success) and erythromycin in relation to ß-lactam and macrolide consumption in Spain over a 19 year period (19791997).
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Materials and methods |
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Macrolides were grouped according to their usual dosage regimen into those taken four or three times a day (tid) (erythromycin, oleandomycin and spiramycin), twice a day (bid) (clarithromycin, roxithromycin, mydecamycin and josamycin) and once a day (od) (azithromycin and dirithromycin). ß-Lactams were grouped into oral or parenteral aminopenicillins, cephalosporins and narrow-spectrum penicillins (penicillins G and V, and methicillin-related penicillins). DDD/1000 inhabitants/day (DID) was calculated using in the denominator the yearly projections of the Spanish population obtained from official data (National Statistics Institute).
For each study identified, the year-specific prevalence of resistance was obtained. For each year, the prevalences of resistance from different studies were combined to obtain an overall estimate. A fixed effects model with weights equal to the inverse of the variances of the prevalence was used to obtain the combined estimates. The prevalence of resistance and the consumption of antibiotics were plotted against each year in the study period. Spearman nonparametric correlation coefficients (r) between the prevalence of resistance and the consumption of macrolides and ß-lactams were calculated. Confidence intervals were calculated by the exact method. To analyse the problem we studied the correlation between global macrolide consumption and the prevalence of erythromycin resistance, as well as the global consumption of ß-lactams and the prevalence of both intermediate and high-level penicillin resistance. In addition, the cross correlation between both ß-lactam consumption with erythromycin resistance, and macrolide consumption with penicillin resistance was studied. Afterwards, the association between consumption of specific macrolide or ß-lactam antibiotics with the prevalence of erythromycin, and high and intermediate levels of penicillin resistance, respectively, were analysed separately. Variables in the stepwise multiple linear regression modelling included those associated with resistance in the univariate analysis (P < 0.1). The SPSS for Windows Release 7.5 statistical package was used to carry out the analyses.
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Results |
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In the macrolide univariate model a different strength of association between erythromycin resistance and consumption of the three different macrolide groups was observed. The correlation coefficients were 0.772, 0.810 and 0.905 for od, tid and bid macrolide consumption, respectively (P < 0.001) (Figure 1). When the multivariate analysis was performed the variable that best fit with the evolution of erythromycin resistance was the consumption of bid macrolides (adjusted r2 = 0.886; P < 0.01; standardized ß coefficient = 0.945).
A significant association was also obtained between global ß-lactam consumption and penicillin non-susceptibility (MIC 0.12 mg/L; r = 0.973), owing to the correlation with high-level penicillin resistance (MIC
2 mg/L; r = 0.948) but not with the intermediate-level penicillin resistance (r = 0.430).
At study baseline (1979), penicillin non-susceptibility (MIC 0.12 mg/L) prevalence was low (5.6%, IC95 = 2.610.3) and increased progressively until 1997 (59.6%, IC95 = 55.363.7). The prevalence of penicillin-intermediate strains reached a peak in the 19881991 period and since then it has decreased slightly behaving in a fairly stable manner (at around 20%); in contrast, high-level resistance (MIC
2 mg/L) prevalence has been increasing at a constant pace since the beginning, until 1997 (37.7%, IC95 = 33.641.9), surpassing the prevalence of intermediate-level penicillin resistance in 1992 for the first time (25.3% versus 17.5%). The steady increase in global penicillin resistance (MIC
0.12 mg/L) from 1992 onwards was due to the increase in the prevalence of high-level resistance, which compensated for the decrease in penicillin-intermediate strains (Figure 2
).
As far as the ß-lactam univariate model is concerned, a highly significant association (r > 0.8; P < 0.001) was found between high-level penicillin resistance and the increase in the consumption of oral aminopenicillins (r = 0.940), oral cephalosporins (r = 0.936) and oral narrow-spectrum penicillins (r = 0.940), but not with parenteral consumption of cephalosporins (r = 0.747), aminopenicillins or narrow-spectrum penicillins (the two latter showed r < 0). Regarding intermediate-level penicillin resistance no association (r < 0.5) was observed for the consumption of any antibiotic group, either oral or parenteral.
In the multivariate analysis for high-level penicillin resistance, the variable that best fit the observed change in high-level penicillin resistance rate over time was the consumption of oral cephalosporins (adjusted r2 = 0.877; P < 0.01; standardized ß coefficient = 0.940).
In addition to this correlation of resistance to a class of antimicrobial with its own usage, total ß-lactam consumption also correlated with erythromycin resistance (r = 0.942), and total macrolide consumption correlated with penicillin non-susceptibility (r = 0.957) owing again to high-level penicillin resistance (r = 0.915), but not with intermediate-level penicillin resistance prevalence (r = 0.467).
A strong association was observed between the increase in high-level penicillin resistance and erythromycin resistance (r = 0.903; P < 0.001).
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Discussion |
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The relationship between erythromycin resistance (as a marker of macrolide resistance) and total macrolide consumption (r = 0.942) could apparently be explained by the fact that in the multivariate analysis the consumption of bid macrolides was the best fit variable for the evolution of erythromycin resistance (adjusted r2 = 0.886), accounting for up to 88.6% of the observations. Actually, some authors have already discussed that on a pharmacokinetic and pharmacodynamic basis, long-acting macrolides (with low Cmax and long half-life) may optimize selection of erythromycin resistance.3,27 However, the drop in tid macrolide consumption in the period from 19921997 was clearly compensated by the surge of bid and od macrolides, and hence two additional possible interpretations of these results may be suggested. (i) The total consumption of macrolides may be what really matters. The introduction into use of bid + od macrolides may have increased the total macrolide consumption beyond a certain critical threshold (around 2 DDD/1000 inhabitants/day) needed for effective selection of erythromycin resistance. In our analysis, as erythromycin resistance is related to total macrolide consumption, macrolides that are used most commonly, i.e. bid macrolides, provide the greatest relationship to erythromycin resistance because they represent the greatest amount of macrolide use. (ii) The possibility of coselection of strains. Coselection should be taken into account because a significant correlation between global ß-lactam consumption and the prevalence of erythromycin resistance (r = 0.942) was found, which is in accord with previous reports of the association of high-level penicillin resistance and erythromycin resistance.4,28,29
Again, with ß-lactams three possibilities arise: (i) high-level penicillin resistance relates to global ß-lactam consumption (r = 0.948); (ii) the potential for increasing the prevalence of high-level penicillin resistance by the consumption of different ß-lactam antibiotics varies between the specific compounds and their route of administration; (iii) consumption of macrolides coselects high-level penicillin resistance.
Regarding the first possibility, global ß-lactam consumption relates to the prevalence of high-level penicillin resistance (r = 0.948) but not to the intermediate level of resistance as discussed below.
With respect to the second possibility, the fact that oral cephalosporin consumption explains up to 87.7% (adjusted r2 = 0.877) of the temporal evolution of high-level penicillin resistance prevalence, despite its DIDs being almost three times less than those of oral aminopenicillins, is also very interesting. As shown in Figure 2, the inversion in prevalence for highly (MIC
2 mg/L) and intermediately (MIC 0.121 mg/L) resistant strains became evident after the increase in oral cephalosporin consumption. This observation is in accord with previous in vitro experiments of selection of resistance where aminopenicillins were good selectors for a low level of resistance, cefuroxime was a good selector of high-level resistance and cefixime was the best resistance selector,26 probably due to the pharmacodynamic characteristics and selective antibiotic concentrations of the antibiotic. It is worth noting that no association between consumption of any ß-lactam group and the evolution of penicillin-intermediate resistance was found. However, we should bear in mind that this absence of association (expressed as a rate at a determinate time-point), has to be seen only from a population ecological perspective, since for a high-level penicillin resistance to develop usually a previous intermediate-level penicillin resistance is required.
In Spain, since the first report in 1981 of a pneumococcal strain with a penicillin MIC of 0.16 mg/L30 and several other reports afterwards, low-level penicillin resistance prevalence became evident. This may have been due to penicillin's ability to select low-level resistance,26 since at that time oral cephalosporins were hardly available. Data of this study seem to point out that the consumption of oral cephalosporins is more likely to increase the prevalence of high-level penicillin resistance among pneumococci than the consumption of oral aminopenicillins.
As a third possibility the question arises as to whether macrolide use could increase penicillin resistance. Recent epidemiological surveys4,28,29 show that penicillin non- susceptible pneumococci are also more likely to be resistant to either macrolidesazalides or oral cephalosporins. Furthermore, as is the case with ß-lactam consumption, which seems to be able to increase resistance to erythromycin, we have also found that global macrolide consumption correlates (r = 0.915) with high-level penicillin resistance. The coselection may imply an important epidemiological factor in the evolution of resistance over time and it would have been desirable to study the prevalence of co-resistance (to penicillin plus erythromycin) over time. Unfortunately, this was not feasible because most of the papers reviewed in this study do not indicate the number of pneumococcal strains showing both types of resistance.
Our study has obviously some important but unavoidable flaws. Its retrospective, literature-based nature imposes certain limitations on the consistency of sampled populations between the different studies at different times and weakens in some way the conclusions drawn since we cannot assess the specific weight of each of the three possibilities for both ß-lactams and macrolides stated above. However, we do think that the criteria applied in the selection of the 20 studies included have been strict enough to ensure as little inconsistency as possible.
As far as consumption is concerned, the IMS database takes a representative sample of pharmacies and then extrapolates data to a national level. Of course this implies a certain simplification of the complex geographical and seasonal reality of antibiotic consumption. Ideally, antibiotic usage in particular communities should be correlated with the prevalence of resistance locally, but unfortunately this information was not available.
Some may also argue that our DDD values assigned to certain antibiotics on the basis of country or local differences in therapy for the same indications are not exactly those recommended by WHO. Nevertheless, DDD values do not affect at all the internal strength of the association between consumption and resistance because we are focusing on trends over time and not on single time-point values.31
Although this ecological analysis cannot establish a causal relationship between antibiotic consumption and development of resistance, the data are consistent with the hypothesis that overuse of certain antibiotics, namely oral cephalosporins and bid macrolides, seem to have had a greater responsibility than use of other antibiotics for the increase of drug-resistant strains of S. pneumoniae in Spain in the last 19 years. Specific active intervention studies in closed communities targeting the antibiotics more likely to be responsible for the resistances and then following both penicillin and macrolide resistance levels, are needed in order to ascertain whether a policy limiting the prescription of those antibiotics more likely to select (or coselect) resistance, or even those not active enough in the current environment of growing non-susceptibility to macrolides or ß-lactams, would be worthwhile.
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Acknowledgments |
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Notes |
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References |
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Received 30 March 2000; returned 15 June 2000; revised 28 June 2000; accepted 12 July 2000