β-Lactam Effects on Mixed Cultures of Common Respiratory Isolates as an Approach to Treatment Effects on Nasopharyngeal Bacterial Population Dynamics

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.

Update on the clinical utility and optimal use of cefditoren

“…However, clinical failures of penicillin/amoxicillin treatment derived from indirect protection of S. pyogenes by β-lactamases produced by M. catarrhalis or H. influenzae have been reported 88. Indirect protection of S. pyogenes could also affect amoxicillin/clavulanic acid efficacy when BLPACR strains are present, as has occurred in vitro 66. Oral β-lactams resistant to β-lactamases such as cefditoren could offer advantages by countering indirect pathogenicity, although clinical effects of indirect pathogenicity have been criticized by some authors 89,90…”

Cefditoren in upper and lower community-acquired respiratory tract infections

“…Co-pathogenicity was also explored in vitro in a pharmacodynamic simulation of free concentrations over 24 hours obtained with 875 mg amoxicillin 3 times daily, 875/125 mg amoxicillin/clavulanic acid 3 times daily, and 400 mg cefditoren twice daily using individual and mixed inocula (proportions 1:1:1:1) of 1 S. pyogenes isolate, 1 penicillin-resistant S. pneumoniae , 1 β-lactamase positive H. influenzae , and 1 BLPACR H. influenzae isolate 66. At 24 hours amoxicillin was able to eradicate S. pyogenes in simulations carried out with the individual S. pyogenes inoculum but failed to do so in simulations with the mixed inocula where S. pyogenes was protected by β-lactamases produced by the H. influenzae isolates 66. In contrast S. pyogenes was eradicated by cefditoren, both in individual and mixed simulations where both strains of H. influenzae were also eradicated 66…”

Gaps in antibiotic development: the postmarketing task

“…Among others, these models could also be used to explore the effects of physiological concentrations attained with a new formulation against nonsusceptible strains to the antibiotic [15], to explain clinical failures and determine the value of PK/PD parameters needed to prevent the emergence of resistant subpopulations [16], to study the potential influence of the infection site on PK/ PD prediction [17] and to study the adequacy of different PK/PD values obtained with different infusion regimens in the face of resistance [18]. In relation to ecological population dynamics and resistance in human microbiota, simulations can also be used to predict selection of resistance in multibacterial niches (simulating the nasopharynx), whether selection of resistant strains in niches with multiple strains of the same species [19] or resistant subpopulations within a strain [20] or both, or resistant strains in a niche with multiple strains of different species [21]. Thus, the data provided by these models may be a tool to predict the future spread of resistance.…”