Bacteriological efficacies of three macrolides compared with those of amoxicillin-clavulanate against Streptococcus pneumoniae and Haemophilus influenzae

Abstract

Comparative antibacterial efficacies of erythromycin, clarithromycin, and azithromycin were examined against Streptococcus pneumoniae and Haemophilus influenzae, with amoxicillin-clavulanate used as the active control. In vitro, the macrolides at twice their MICs and at concentrations achieved in humans were bacteriostatic or reduced the numbers of viable S. pneumoniae slowly, whereas amoxicillin-clavulanate showed a rapid antibacterial effect. Against H. influenzae, erythromycin, clarithromycin, and clarithromycin plus 14-hydroxy clarithromycin at twice their MICs produced a slow reduction in bacterial numbers, whereas azithromycin was bactericidal. Azithromycin at the concentrations achieved in the serum of humans was bacteriostatic, whereas erythromycin and clarithromycin were ineffective. In experimental respiratory tract infections in rats, clarithromycin (equivalent to 250 mg twice daily [b.i.d.]) and amoxicillin-clavulanate (equivalent to 500 plus 125 mg b.i.d., respectively) were highly effective against S. pneumoniae, but azithromycin (equivalent to 500 and 250 mg once daily) was significantly less effective (P < 0.01). Against H. influenzae, clarithromycin treatment (equivalent to 250 or 500 mg b.i.d.) was similar to no treatment and was significantly less effective than amoxicillin-clavulanate treatment (P < 0.01). Azithromycin demonstrated significant in vivo activity (P < 0.05) but was significantly less effective than amoxicillin-clavulanate (P < 0.05). Overall, amoxicillin-clavulanate was effective in vitro and in vivo. Clarithromycin and erythromycin were ineffective in vitro and in vivo against H. influenzae, and azithromycin (at concentrations achieved in humans) showed unreliable activity against both pathogens. These results may have clinical implications for the utility of macrolides in the empiric therapy of respiratory tract infections.

FIG. 1

Diagrammatic representation of the in vitro pharmacodynamic model.

FIG. 2

Bactericidal activities of erythromycin (•), clarithromycin (■), clarithromycin plus 14-hydroxy clarithromycin (1:1) (□), azithromycin (▴), and amoxicillin-clavulanate (⧫) at twice the MICs compared with the results for untreated control cultures (×) of S. pneumoniae ATCC 6303 (a) and H. influenzae LH2803 (b).

FIG. 3

Concentrations of antibiotic achieved in the serum of humans following the administration of oral doses of 250 mg of erythromycin (•) (21), 250 mg of clarithromycin (clarithromycin plus 14-hydroxy clarithromycin) (■) (9), 500 mg of azithromycin (▴) (11), and 500 mg of amoxicillin (⧫) (18) and concentrations achieved in the pharmacokinetic model used to simulate these data (open symbols).

FIG. 4

Bactericidal activities of simulated concentrations achieved in the serum of humans following the administration of oral doses of 250 mg of erythromycin (•), 250 mg of clarithromycin (■), 500 mg of azithromycin (▴), 500 and 125 mg of amoxicillin and clavulanate, respectively (⧫), and 500 mg of amoxicillin (◊) compared with the results for untreated control cultures (×) of S. pneumoniae ATCC 6303 (a) and H. influenzae LH2803 (b).

FIG. 5

Efficacies of amoxicillin (AMX) given at 200 mg/kg b.i.d., amoxicillin-clavulanate (AMX/CA) given at 200 plus 50 mg/kg, respectively, b.i.d., azithromycin (AZI) given at 20 and then 10 mg/kg o.d., and clarithromycin (CLA) given at 20 mg/kg b.i.d. against respiratory tract infection in rats caused by S. pneumoniae 1629. Each circle represents an animal. Closed circles represent animals that died before the end of the study.

FIG. 6

Efficacies of amoxicillin (AMX) given at 200 mg/kg b.i.d., amoxicillin-clavulanate (AMX/CA) given at 200 plus 50 mg/kg, respectively, b.i.d., clarithromycin (CLA) given at 20 mg/kg b.i.d., clarithromycin (CLA+) given at 40 mg/kg, and erythromycin (ERY) given at 100 mg/kg against respiratory tract infection in rats caused by H. influenzae H128. Each circle represents an animal. The closed circle represents an animal that died before the end of the study.

FIG. 7

Efficacies of amoxicillin (AMX) given at 200 mg/kg b.i.d., amoxicillin-clavulanate (AMX/CA) given at 200 plus 50 mg/kg, respectively, b.i.d., and azithromycin (AZI) given at 20 and then 10 mg/kg o.d. against respiratory tract infection in rats caused by H. influenzae H128. Each circle represents an animal.