Effects of Specific Antibodies against Streptococcus pneumoniae on Pharmacodynamic Parameters of β-Lactams in a Mouse Sepsis Model

Abstract

A dose-ranging study to investigate the in vivo effects of the presence of specific antibodies on the efficacy of ␤-lactam treatment of sepsis caused by Streptococcus pneumoniae (non-␤-lactam-susceptible serotype 6B isolate) was performed with a BALB/c mouse model. Hyperimmune serum was obtained from mice immunized with the heat-inactivated strain. The rate of mortality was 100% in nontreated animals in the absence of specific antibodies. A single injection of a one-half or one-quarter dilution of hyperimmune serum produced 60 to 40% survival rates. In the absence of specific antibodies, the minimal effective doses of amoxicillin and cefotaxime that produced survival rates of 100 and 80% were 25 and 50 mg/kg of body weight (three times a day for up to six doses), respectively. These doses produced times that the levels in serum remained above the MIC (⌬T > MICs) Ϸ30% of the dosing interval. When specific antibodies were present (by administration of a one-half or one-quarter dilution of hyperimmune serum), the minimal effective doses of the antibiotics were 3.12 and 6.25 mg/kg (Ϸ8 times lower), with the ⌬T > MICs being approximately 3 and 5% of the dosing interval for amoxicillin and cefotaxime, respectively. This in vivo combined pharmacodynamic effect offers possibilities that can be used to address penicillin resistance.Evidence shows that the successful outcome of infections caused by Streptococcus pneumoniae in humans depends on the humoral arm of the immune system and on treatment with an adequate antibiotic. Immunogenicity depends on the pneumococcal serotype (11). Evidence of the participation of immunogenicity in the outcome is based on the spontaneous resolution of fever in the absence of treatment at the time that capsular antibodies appear (15) and the increase in the severities of infections when immunoglobulin G2 (IgG2) (10) or C3 complement (4) deficiencies are present.Colonization with S. pneumoniae is an immunizing event. In the absence of conditions that predispose an individual to infection, antibodies to the capsular polysaccharide of a colonizing organism are likely to appear before infection (15). The presence of anticapsular antibodies is regarded as a generally good, but not ideal, surrogate marker of immunity; the absence of such antibodies probably indicates a relative degree of susceptibility, even though many other factors contribute to protection against pneumococcal disease (15). In these circumstances, the appearance of pneumococcal sepsis indicates defective protection against pneumococcal invasion.The administration of serum containing type-specific antibodies in the preantibiotic era was only moderately effective for the treatment of pneumococcal pneumonia (15) and was largely supplanted by the administration of antibiotics. Empirical antibiotic treatment should be chosen by consideration of data from susceptibility surveillance studies (1), antibiotic susceptibility profiles for isolates of a particular serotype (5, 6, 13), serotype distribution (5, 6, 13), and the disease bein...

LysGH15, a Novel Bacteriophage Lysin, Protects a Murine Bacteremia Model Efficiently against Lethal Methicillin-Resistant Staphylococcus aureus Infection

“…Once the MLD had been determined, 2ϫ MLD was used as the infective inoculum (challenge dose). The procedure for this experiment was carried out as described previously, with modifications (3,20).…”

Effects of Amoxicillin Subinhibitory Concentrations on the Cross-Protection Developed by Pneumococcal Antibodies in Mouse Sepsis Caused by an Amoxicillin-Resistant Serotype 6BStreptococcus pneumoniaeStrain

“…In previous studies (2,21,22), a synergistic effect between the 3.12-mg/kg subtherapeutic dose and the 1/4 dilution of hyperimmune serum specific to the infecting strain, a 6B non-amoxicillin-resistant (amoxicillin MIC of 4 g/ml) S. pneumoniae strain (different from the serotype 6B strain used in the present study), with respect to mortality, was not clearly demonstrated due to the high protection provided by immunization. With respect to synergism, the more interesting interactions are those that result in enhanced rates or absolute magnitudes of bacterial killing by the combination compared with those by either drug alone (8), and it has been proposed that this effect be measured in vivo (17).…”

“…Amoxicillin concentrations in serum in six healthy animals after a single subcutaneous dose of antibiotic were determined as previously described (2) to confirm the concentrations determined in previous experiments (2).…”

“…Amoxicillin doses were selected based on the results of a previous study (2). The dose of 3.12 mg/kg of body weight was chosen to assure subinhibitory concentrations in serum over the entire treatment period, and the 25-mg/kg dose was chosen as a positive therapeutic control of antibiotic efficacy.…”

“…This fact is important if, as in previous studies (2,21,22), animals have been passively immunized with hyperimmune serum obtained after serial immunizations with a whole-cell pneumococcal heat-inactivated inoculum, leading to the probability of participation of antibodies other than those directed to the serotype-specific polysaccharide. In these studies (2,21,22), the protection obtained by passive immunization with hyperimmune serum was elevated, and, with the addition of antibiotic treatment, the combined effect was similar to the addition of effects obtained by the administration of hyperimmune serum and the antibiotic alone, thus suggesting an additive effect.…”