Response of Streptococcus pyogenes to therapy with amoxicillin or amoxicillin-clavulanic acid in a mouse model of mixed infection caused by Staphylococcus aureus and Streptococcus pyogenes

Abstract

The response of Streptococcus pyogenes to amoxicillin or amoxicillin-clavulanic acid (Augmentin; Beecham Group) therapy of a mixed streptococcal-staphylococcal infection was studied in a surgical wound in mice. A superficial wound was produced on the backs of anesthetized mice, and a suture infected with S. pyogenes, Staphylococcus aureus, or a mixed inoculum of both organisms was inserted. Oral therapy was started 4 h after infection and continued for 3 days. Both amoxicillin and amoxicillin-clavulanic acid were effective in eliminating the streptococci from the pure wound infection. In contrast, amoxicillin failed to eliminate the streptococci from a mixed infection in which a ,-lactamase-producing strain of S. aureus was also present, wound counts reaching 107 streptococci per wound by 80 h, whereas amoxicillin-clavulanic acid reduced the count to <33 streptococci per wound by 24 h. Numbers of S. aureus were also reduced by amoxicillin-clavulanic acid therapy, controlling the infection, whereas amoxicillin was ineffective. Also of significance was the fact that successful therapy was achieved with blood and tissue concentrations of amoxicillin and clavulanic acid of the same order as those measured in humans. These results show that amoxicillin therapy failed to eliminate S.pyogenes from a wound infection in the presence of a P-lactamase-producing strain of S. aureus and suggest the potential of amoxicillin-clavulanic acid in the treatment of mixed bacterial skin infections involving P3-lactamase-producing organisms.

Establishment of a Superficial Skin Infection Model in Mice by Using Staphylococcus aureus and Streptococcus pyogenes

“…In contrast to previously described models for skin infection (1,5,14,32,36), the infection route in our model is topical. Partial removal of the epidermal layer of the skin allowed both S. aureus and S. pyogenes to colonize the skin and to elicit a profound inflammatory response.…”

“…The tape-stripping model has been developed to test the effectiveness of topical antibiotic treatments of superficial skin infections caused by Staphylococcus aureus or Streptococcus pyogenes. S. aureus and S. pyogenes are the most common causative agents of primary skin infections in humans (11,17).The existing mouse models for topical treatment of skin infections are the burnt skin model (1, 32, 36) and the skin suture-wound model (5,14). Either the bacteria are introduced into the skin by injection in a traumatized skin area, as in the burnt skin model, or a bacterium-impregnated nylon suture is implanted into an artificial wound (a scalpel incision through all skin layers), which is then sewn or stapled shut, as in the skin suture-wound model.…”

“…Antibiotics dissolved in cream or ointment can be applied to the wound during the course of the experiment. At the experimental end point, the animal is killed, the infected area of the skin is cut out, and the number of bacteria in the sample is assayed (1,5,14,32,36). These mouse models for skin infections have some disadvantages in relation to superficial infections.…”

“…The existing mouse models for topical treatment of skin infections are the burnt skin model (1, 32, 36) and the skin suture-wound model (5,14). Either the bacteria are introduced into the skin by injection in a traumatized skin area, as in the burnt skin model, or a bacterium-impregnated nylon suture is implanted into an artificial wound (a scalpel incision through all skin layers), which is then sewn or stapled shut, as in the skin suture-wound model.…”

Influence of clavulanic acid on the activity of amoxicillin against an experimental Streptococcus pneumoniae-Staphylococcus aureus mixed respiratory infection

“…In the majority of the cases reported, initial penicillin therapy directed against S. pneumoniae failed because of the presence of P-lactamase-producing staphylococci, which now account for more than 90% of community-acquired strains of S. aureus (9). The failure of penicillin therapy to eradicate penicillin-susceptible pathogens in the presence of ,B-lactamase-producing bacteria has been reported for a number of clinical situations (4,14,16).The objective of this study was to develop an experimental model of mixed respiratory infection caused by a penicillinsusceptible strain of S. pneumoniae and a P-lactamaseproducing strain of S. aureus, in order to study the role of the P-lactamase inhibitor clavulanic acid in such a situation.Clavulanic acid is a potent inhibitor of a wide range of bacterial P-lactamases, including those produced by S. aureus (18,19), and has been reported to protect amoxicillin from inactivation by the f-lactamase activities of mixed bacterial cultures which are refractory to this penicillin in vitro and in vivo (2,5,22 Organisms. S. aureus MB9, a P-lactamase-producing strain, and S. pneumoniae 1629, a penicillin-susceptible strain, were used.…”