BackgroundSpecific antibodies mediate humoral and cellular protection against invading pathogens such as Streptococcus pneumoniae by activating complement mediated immunity, promoting phagocytosis and stimulating bacterial clearance. The emergence of pneumococcal strains with high levels of antibiotic resistance is of great concern worldwide and a serious threat for public health.Methodology/Principal FindingsFlow cytometry was used to determine whether complement-mediated immunity against three antibiotic-resistant S. pneumoniae clinical isolates is enhanced in the presence of sub-inhibitory concentrations of cefditoren and ceftriaxone. The binding of acute phase proteins such as C-reactive protein and serum amyloid P component, and of complement component C1q, to pneumococci was enhanced in the presence of serum plus either of these antibiotics. Both antibiotics therefore trigger the activation of the classical complement pathway against S. pneumoniae. C3b deposition was also increased in the presence of specific anti-pneumococcal antibodies and sub-inhibitory concentrations of cefditoren and ceftriaxone confirming that the presence of these antibiotics enhances complement-mediated immunity to S. pneumoniae.Conclusions/SignificanceUsing cefditoren and ceftriaxone to promote the binding of acute phase proteins and C1q to pneumococci, and to increase C3b deposition, when anti-pneumococcal antibodies are present, might help reduce the impact of antibiotic resistance in S. pneumoniae infections.

The emergence of Streptococcus pneumoniae strains displaying high levels of multidrug resistance is of great concern worldwide and a serious threat for the outcome of the infection. Modifications of the bacterial envelope by antibiotics may assist the recognition and clearance of the pathogen by the host immune system. Recognition of S. pneumoniae resistant strains by the complement component C3b was increased in the presence of specific anti-pneumococcal antibodies and subinhibitory concentrations of different macrolides and ␤-lactam antibiotics for all the strains investigated. However, C3b levels were unchanged in the presence of serum containing specific antibodies and sub-MICs of levofloxacin. To investigate whether LytA, the main cell wall hydrolase of S. pneumoniae, might be involved in this process, lytA-deficient mutants were constructed. In the presence of antibiotics, loss of LytA was not associated with enhanced C3b deposition on the pneumococcal surface, which confirms the importance of LytA in this interaction. The results of this study offer new insights into the development of novel therapeutic strategies using certain antibiotics by increasing the efficacy of the host immune response to efficiently recognize pneumococcal resistant strains. Streptococcus pneumoniae, also termed pneumococcus, is the leading bacterial cause of acute otitis media in children, community-acquired pneumonia, and nonepidemic meningitis and a frequent cause of bacteremia (15). Despite appropriate antibiotic treatment, invasive pneumococcal disease (IPD) is a very common infection associated with high rates of morbidity and mortality worldwide. The widespread use of antibiotics has been one of the major reasons for the emergence of clinical isolates that exhibit resistance to multiple antibiotics. A major threat to fighting IPD is the appearance of strains harboring high levels of antibiotic resistance, as has been recently reported in Europe (19). The development of resistance to a wide variety of antimicrobial drugs has allowed S. pneumoniae to attain the status of a so-called "superbug" (11). The complement system is one of the first lines of defense against invading pathogens, such as S. pneumoniae, with an essential role in both innate and adaptive immunity (23). Activation of complement cascades leads to the formation of the key component C3b, which is crucial in host defense against pneumococcus by coating the microorganism and stimulating phagocytosis (23). In cases where the invading pathogen displays multidrug resistance, antimicrobial concentrations in serum may be insufficient, and therefore, the outcome of the infection largely depends on the interaction between bacterial virulence factors and host immune mechanisms. Using mice infected with a pneumococcal resistant strain and treated with subtherapeutic doses of ␤-lactam antibiotics, we previously found that bacterial clearance and survival were increased in mice immunized against S. pneumoniae, suggesting a synergistic effect between antimicrobial chemother...