No abstract

A nationwide multicenter susceptibility surveillance study which included 1,684 Streptococcus pneumoniae and 2,039 S. pyogenes isolates was carried out over 1 year in order to assess the current resistance patterns for the two most important gram-positive microorganisms responsible for community-acquired infections in Spain. Susceptibility testing was done by a broth microdilution method according to National Committee for Clinical Laboratory Standards M100-S10 interpretative criteria. For S. pneumoniae, the prevalences of highly resistant strains were 5% for amoxicillin and amoxicillin-clavulanic acid; 7% for cefotaxime; 22% for penicillin; 31% for cefuroxime; 35% for erythromycin, clarithromycin, and azithromycin; and 42% for cefaclor. For S. pyogenes, the prevalence of erythromycin resistance was 20%. Efflux was encountered in 90% of S. pyogenes and 5% of S. pneumoniae isolates that exhibited erythromycin resistance. Erythromycin resistance was associated with clarithromycin and azithromycin in both species, regardless of phenotype. Despite the different nature of the mechanisms of resistance, a positive correlation (r ‫؍‬ 0.612) between the two species in the prevalence of erythromycin resistance was found in site-by-site comparisons, suggesting some kind of link with antibiotic consumption. Regarding ciprofloxacin, the MIC was >4 g/ml for 7% of S. pneumoniae and 3.5% of S. pyogenes isolates. Ciprofloxacin resistance (MIC, >4 g/ml) was significantly (P < 0.05) associated with macrolide resistance in both S. pyogenes and S. pneumoniae and with penicillin nonsusceptibility in S. pneumoniae.

The sequence of the ftsI gene encoding the transpeptidase domain of penicillin-binding protein 3 (PBP 3) was determined for 354 nonconsecutive Haemophilus influenzae isolates from Spain; 17.8% of them were ampicillin susceptible, 56% were ␤-lactamase nonproducing ampicillin resistant (BLNAR), 15.8% were ␤-lactamase producers and ampicillin resistant, and 10.4% displayed both resistance mechanisms. The ftsI gene sequences had 28 different mutation patterns and amino acid substitutions at 23 positions. Some 93.2% of the BLNAR strains had amino acid substitutions at the Lys-Thr-Gly (KTG) motif, the two most common being Asn526 to Lys (83.9%) and Arg517 to His (9.3%). Amino acid substitutions at positions 377, 385, and 389, which conferred cefotaxime and cefixime MICs 10 to 60 times higher than those of susceptible strains, were found for the first time in Europe. In 72 isolates for which the repressor acrR gene of the AcrAB efflux pump was sequenced, numerous amino acid substitutions were found. Eight isolates with ampicillin MICs of 0.25 to 2 g/ml showed changes that predicted the early termination of the acrR reading frame. Pulsed-field gel electrophoresis analysis demonstrated that most BLNAR strains were genetically diverse, although clonal dissemination was detected in a group of isolates presenting with increased resistance to cefotaxime and cefixime. Background antibiotic use at the community level revealed a marked trend toward increased amoxicillin-clavulanic acid consumption. BLNAR H. influenzae strains have arisen by vertical and horizontal spread and have evolved to adapt rapidly to the increased selective pressures posed by the use of oral penicillins and cephalosporins.

A geographical analysis of how commonly prescribed oral antibiotics are quantitatively and qualitatively responsible for the different local rates of erythromycin and penicillin resistance in Streptococcus pneumoniae in Spain is presented. From 1998 to 1999 a multicenter surveillance study yielded 1,684 consecutive S. pneumoniae isolates from community-acquired respiratory infections. Data on antibiotic sales in the retail market for the same period were gathered, and the corresponding defined doses per 1,000 inhabitants per day were calculated. Macrolides and ␤-lactams were considered separately. Macrolides were subdivided into thrice-, twice-, and once-a-day macrolides, and ␤-lactams were split into aminopenicillins and cephalosporins. Univariate Spearman nonparametric coefficients (R) were calculated, and variables proving to be significantly associated (P < 0.1) were entered into several multiple lineal regression models. Ample variation in both resistance rates and antibiotic consumption was seen. Multivariate analyses showed that integrated consumption of both macrolides and ␤-lactams accounted well for erythromycin (R 2 ‫؍‬ 0.722; P ‫؍‬ 0.002) and penicillin (R 2 ‫؍‬ 0.706; P ‫؍‬ 0.002) resistance. Macrolides were more important drivers for local differences in both erythromycin and penicillin resistance than ␤-lactams were. Consumption of once-a-day macrolides was key for local erythromycin resistance variations. Cephalosporins were slightly more important penicillin resistance drivers than aminopenicillins were.The increasing development of resistance in Streptococcus pneumoniae not only to a single antibiotic but to many antibiotics at the same time (5) (multiresistant S. pneumoniae) is a striking example of the evolutionary adaptability of bacterial populations to antibiotic action. Antibiotics seem to have selected specific subpopulations resistant to the antibiotics frequently prescribed for common infections.The development and subsequent spread of resistant pneumococci do not follow the same pace in different regions of the world. While in Northern European countries, rates of resistance to erythromycin and penicillin remain low, in Spain, France, Hong Kong and certain U.S. states, these rates may be above 50% (5). However, even in low-risk countries, a steady progression of resistance over recent years is being observed (1, 2, 12).Antibiotics are increasingly recognized as the leading force in this growth of resistance (8,9,11,20). Nevertheless, studies performed so far to confirm this issue can only indirectly support the hypothesis of antibiotic consumption as the main driver for resistance differences. Even studies exploring the temporal coincidence between increased antibiotic consumption and resistance do not provide straightforward causal evidence. If the hypothesis is correct, then a positive correlation between antibiotic use in a given location and the corresponding prevalence of resistance should be expected. The aim of this study was to explore this hypothesis as well as to try to asce...