In vitro antagonism between beta-lactam and macrolide in Streptococcus pneumoniae: how important is the antibiotic order?

We found that the in vitro interaction between penicillin or cefotaxime and erythromycin against Streptococcus pneumoniae varies depending on the order of antibiotic exposure. Time-kill experiments were performed with penicillin, cefotaxime, erythromycin and different order combinations of both beta-lactams with erythromycin. The mean difference between the colony count at 0 and 6h for penicillin, cefotaxime and erythromycin tested separately was 3.5 log cfu/mL, 2.4 and 1.5 respectively for susceptible strains. The mean difference for the combination of beta-lactam and erythromycin studied simultaneously was 1.8 log cfu/mL for these strains. The association of penicillin or cefotaxime with erythromycin added two hours later showed an activity similar to those of beta-lactam alone (mean difference was 3.0 for this association with penicillin and 2.5 with cefotaxime). Therefore, the antagonistic effect of macrolide activity could be less important if erythromycin was administrated after beta-lactam.

In vitro activity of cefodizime (HR-221) in combination with beta-lactamase inhibitors.

Cefodizime (formerly HR221) was tested either for in vitro microbiological activity or for its stability to beta-lactamases in the presence of two beta-lactamase inhibitors (clavulanic acid, tazobactam). Cefodizime was a poor substrate of class C enzymes but hyperproducer strains were generally resistant with or without a beta-lactamase inhibitor used in combination. On the contrary, class A enzymes were able to hydrolyze cefodizime. However, strains expressing class A beta-lactamase were susceptible to cefodizime in combination with clavulanic acid.

Antagonistic effect of chloramphenicol in combination with cefotaxime or ceftriaxone.

We evaluated the in vitro interaction at clinically attainable concentrations of cefotaxime and ceftriaxone with chloramphenicol against 26 clinical isolates of gram-negative rods, group B streptococci, and Staphylococcus aureus. Cefotaxime and ceftriaxone were bactericidal against all 26 organisms (MBC, 0.03 to 4 micrograms/ml). Chloramphenicol was bacteriostatic against 24 organisms (MBC, greater than or equal to 32 micrograms/ml) and bactericidal against two Escherichia coli isolates (MBC, 8 micrograms/ml). Checkerboard testing showed chloramphenicol to be antagonistic to the bactericidal activity of cefotaxime and ceftriaxone for all 24 bacteria for which chloramphenicol was bacteriostatic. Time kill curves for selected strains of E. coli and group B streptococci for which chloramphenicol was bacteriostatic showed antagonism of chloramphenicol to both cephalosporins. The combination of chloramphenicol with either cephalosporin was antagonistic in cases in which chloramphenicol was bacteriostatic against the above organisms and should be avoided in the treatment of infections caused by such organisms if bactericidal therapy is desired.

Evaluation of disk approximation and agar dilution induction tests for demonstration of in vitro antagonism of cefotaxime by cefoxitin in Enterobacter species.

Cefoxitin-resistant clinical isolates of Enterobacter spp. demonstrated inducible beta-lactamase activity in 31 of 47 (65.9%) disk approximation tests and in 32 of 52 (63.5%) agar dilution induction tests. Agreement between the two results was only 72.3%, and 80.9% of the strains were positive in at least one induction test. Lack of valid interpretive criteria preclude their routine use in the clinical laboratory.

Cefoxitin sensitivity as a marker for inducible beta-lactamases.

Inducibility of beta-lactamase activity by cefoxitin was examined in 626 gram-negative clinical isolates selected for amoxycillin and cephalothin resistance. The results indicated that precise identification and cefoxitin sensitivity or resistance could be used to predict the inducibility of beta-lactamase. Of 326 organisms from species capable of beta-lactamase induction, induction was shown in 68% and was predictable from the cefoxitin-sensitivity and identification data. No induction of beta-lactamase occurred in the remaining species. A comparison of beta-lactamase activities against cefotaxime, cefoperazone and latamoxef showed that induction of enzyme activity against cefotaxime and cefoperazone occurred at similar rates. Induction of activity against latamoxef did not occur or was minimal with three bacterial species. The data show that of 119 strains of Enterobacteriaceae displaying inducible beta-lactamase, 113 would have been reported as unequivocally sensitive to cefotaxime, 109 as sensitive to cefoperazone and 116 as sensitive to latamoxef if the disk-diffusion technique alone had been used. The majority of Pseudomonas strains examined produced inducible enzyme and they were more resistant to the three cephalosporins tested than were the Enterobacteriaceae.

Antibacterial antagonism of beta-lactam antibiotics in experimental infections.

In vitro, 5 micrograms/ml of cefoxitin induced the highest beta-lactamase activity in Serratia marcescens TMS22, and the drug at this optimal dose required 2 h to increase the enzyme activity. The increasing enzyme activity was found to decline rapidly after the enzyme inducer effect was lost. When antagonism of cefoxitin against another beta-lactam, cefotaxime, was examined in infected granuloma pouch of rats, cefoxitin antagonized the antibacterial activity of cefotaxime administered at 4 and 6 h after cefoxitin (cefoxitin levels in pouch exudate were around 5 micrograms/ml). The antagonism of an enzyme inducer and another antibiotic may be prevented by administering the non-enzyme inducer before the enzyme inducer exerts its inducer effect or after the enzyme inducer level decreases to an ineffective one.

Failure of chloramphenicol and cefotaxime therapy in Klebsiella meningitis: possible role of antibiotic antagonism.

We have described a patient with Klebsiella pneumoniae meningitis who was treated with cefotaxime and chloramphenicol concomitantly, and whose slow initial resolution and subsequent relapse plus in vitro evidence of antagonism of cefotaxime appear to indicate that chloramphenicol interfered with the activity of the cephalosporin. Thus, concomitant use of chloramphenicol should probably be avoided or used advisedly in adults with gram-negative bacillary meningitis susceptible to a third generation cephalosporin.

[Comparison of antimicrobial activity and stability to beta-lactamases of cefoperazone, cefotaxime, lamoxactam and ceftriaxon]. / Vergleichende Untersuchungen zur antimikrobiellen Aktivität und beta-Lactamasebeständigkeit von Cefoperazon, Cefotaxim, Lamoxactam und Ceftriaxon.

Ceftriaxon (Ro 13-9904) is a new cephalosporin, whose structure resembles cefotaxime. This study compares the minimal inhibitory concentrations (MIC-s) of Ceftriaxon, cefoperazone, cefotaxime, lamoxactam and gentamicin against 622 isolates of various Enterobacteriaceae, non-fermenters and Aeromonas hydrophila. Furthermore the minimal bactericidal concentrations (MBC-s) were determined for some organism; additionally destruction of beta-lactamantibiotics in the presence of beta-lactamases was studied by a bioassay technique. The in vitro activity of Ceftriaxon against gramnegative bacteria was found very similar to that of cefotaxime. The susceptibility of Enterobacter sp. to the three cephalosporines was exceeded by lamoxactam while cefoperazone was the most active beta-lactam-antibiotic against Pseudomonas. Lactamases, which inactivated cefotaxime also destroyed Ceftriaxon in a greater extend. No hydrolysis of lamoxactam and cefoperazone occurred by nearly all bacterial extracts tested.