Abstract
Background Streptococcus pneumoniae, Streptococcus pyogenes and Haemophilus influenzae are bacteria present in the nasopharynx as part of normal flora. The ecological equilibrium in the nasopharynx can be disrupted by the presence of antibiotics.Methodology/Principal FindingsA computerized two-compartment pharmacodynamic model was used to explore β-lactam effects on the evolution over time of a bacterial load containing common pharyngeal isolates by simulating free serum concentrations obtained with amoxicillin (AMX) 875 mg tid, amoxicillin/clavulanic acid (AMC) 875/125 mg tid and cefditoren (CDN) 400 mg bid regimens over 24 h. Strains and MICs (µg/ml) of AMX, AMC and CDN were: S. pyogenes (0.03, 0.03 and 0.015), S. pneumoniae (2, 2 and 0.25), a β-lactamase positive H. influenzae (BL+; >16, 2 and 0.06) and a β-lactamase positive AMC-resistant H. influenzae (BLPACR, >16, 8 and 0.06). Mixture of identical 1∶1∶1∶1 volumes of each bacterial suspension were prepared yielding an inocula of ≈4×106 cfu/ml. Antibiotic concentrations were measured both in bacterial and in bacteria-free antibiotic simulations. β-lactamase production decreased AMX concentrations and fT>MIC against S. pneumoniae (from 43.2% to 17.7%) or S. pyogenes (from 99.9% to 24.9%), and eradication was precluded. The presence of clavulanic acid countered this effect of co-pathogenicity, and S. pyogenes (but not BL+ and S. pneumoniae) was eradicated. Resistance of CDN to TEM β-lactamase avoided this co-pathogenicity effect, and CDN eradicated S. pyogenes and H. influenzae strains (fT>MIC >58%), and reduced in 94% S. pneumoniae counts (fT>MIC ≈25%).Conclusions/SignificanceCo-pathogenicity seems to be gradual since clavulanic acid countered this effect for strains very susceptible to AMX as S. pyogenes but not for strains with AMX MIC values in the limit of susceptibility as S. pneumoniae. There is a potential therapeutic advantage for β-lactamase resistant cephalosporins with high activity against streptococci.
Highlights
Carriage of common respiratory isolates as Haemophilus influenzae, Streptococcus pneumoniae and Streptococcus pyogenes depends on multiple factors such as active or passive smoking, crowding or age [1], strain fitness properties [2], specific vaccination [3], and bacterial interference in antibiotic-free niches
In this study we explored the effect of physiological concentrations of three b-lactams on the evolution over time of a bacterial load containing a beta-hemolytic streptococci (S. pyogenes), an alpha-hemolytic streptococci, and two b-lactamase positive H. influenzae strains in the same niche
For amoxicillin significant differences were found between concentrations determined in simulations carried out with the mixed inocula and those measured in bacteria-free simulations
Summary
Carriage of common respiratory isolates as Haemophilus influenzae, Streptococcus pneumoniae and Streptococcus pyogenes depends on multiple factors such as active or passive smoking, crowding or age [1], strain fitness properties [2], specific vaccination [3], and bacterial interference in antibiotic-free niches. The carriage of strains resistant to b-lactams is a source of concern in some countries as Spain where penicillin non-susceptibility in S. pneumoniae reaches 44% isolates in the community [10], and ampicillin resistance in H. influenzae attains 25%, with 80% of these isolates being resistant due to b-lactamase production and 20% due to the BLNAR (b-lactamase negative ampicillin-resistant) phenotype [10] caused by mutations in the ftsI gene [11]. Strains exhibiting both resistant genotypes (TEM- b-lactamase and mutation in the ftsI gene) constitute the BLPACR (b-lactamase positive amoxicillin/clavulanate-resistant) phenotype and have been recently reported as cause of concern [11]. The ecological equilibrium in the nasopharynx can be disrupted by the presence of antibiotics
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