Multiple combination bactericidal antibiotic testing for patients with cystic fibrosis infected with multiresistant strains of Pseudomonas aeruginosa.

We developed a rapid in vitro antibiotic susceptibility test to screen double- and triple-antibiotic combinations for bactericidal activity against 75 multiresistant Pseudomonas aeruginosa isolates referred from 44 cystic fibrosis (CF) patients. When used alone, the most effective intravenous antibiotic, meropenem, was bactericidal against only 44% of the isolates. High-dose tobramycin (200 microg/ml; concentrations achievable by aerosol administration) was bactericidal against 72% of isolates. Adding a second antibiotic significantly improved bactericidal activity. The most effective double-antibiotic combinations contained high-dose tobramycin plus meropenem, piperacillin/tazobactam, or ciprofloxacin, and were bactericidal against 88 to 94% of the isolates. Excluding high-dose tobramycin, the most effective intravenous double-antibiotic combinations contained meropenem plus ciprofloxacin, tobramycin (4 microg/ml), or cefipime, and were bactericidal against 85%, 71%, and 70% of isolates, respectively. Adding a third antibiotic did not significantly improve inhibition in vitro. We conclude that double-antibiotic combinations containing meropenem or high-dose tobramycin show the best bactericidal activity in vitro against multiresistant strains of P. aeruginosa. Addition of a third antibiotic to these double-antibiotic combinations may be unnecessary.

Overview of synergy with reference to double beta-lactam combinations.

Combination antimicrobial therapy is used to expand the bacterial coverage over a single agent, to prevent the emergence of resistant organisms, to decrease toxicity by allowing lower doses of both agents, or for synergy. Synergy is one of the most common of these reasons, especially in serious infections. The introduction of new broad-spectrum beta-lactam antimicrobials has led to their combination in the treatment of seriously ill patients. Whereas a combination of an aminoglycoside and a beta-lactam antimicrobial is frequently synergistic, much less is known about synergy between combinations of beta-lactams. In vitro testing shows most combinations of two beta-lactams to be indifferent or additive in their effects; rarely does synergy occur. Antagonism can sometimes be seen, particularly with combinations involving cefoxitin or imipenem, especially if the treated organism is Enterobacter or Pseudomonas. Results of clinical trials comparing double beta-lactam (DBL) therapy with aminoglycoside/beta-lactam combinations show no difference in clinical response rates. Highly active DBL combinations may substitute for standard aminoglycoside-containing regimens in certain situations, even though they are not reliably synergistic. However, in the treatment of seriously ill patients such combinations may be less desirable.

The effect of sodium salicylate on antibiotic susceptibility and synergy in Klebsiella pneumoniae.

Sodium salicylate was combined with the antibiotics amikacin, aztreonam, cefazolin, cefonicid, cefoperazone, ceftizoxime, norfloxacin, doxycycline, clindamycin, imipenem, mezlocillin and trimethoprim-sulphamethoxazole. The activity of the combinations was tested against encapsulated strains of Klebsiella pneumoniae, which differed markedly in their antibiotic susceptibility. The addition of salicylate (from 2 to 350 mg/l) to cultures increased the MIC of most antimicrobial agents from two- to four-fold, with the exception of imipenem and amikacin. Inhibition by imipenem was largely unchanged, and that of amikacin was increased in the presence of salicylate. The synergy of the combination of cefazolin and amikacin was abolished by salicylate, while the synergistic activity of imipenem and amikacin was significantly increased by salicylate. Doxycycline activity was most severely affected by salicylate as antimicrobial activity was significantly diminished at salicylate levels as low as 5 mg/l. In contrast, significant loss of inhibitory activity with other antimicrobials required at least 100 mg/l of salicylate. The clinical implications of salicylate on the sensitivity of K. pneumoniae to antimicrobials are discussed.

Effect of low concentrations of clavulanic acid on the in-vitro activity of amoxycillin against beta-lactamase-producing Branhamella catarrhalis and Haemophilus influenzae.

Concentrations of amoxycillin/clavulanic acid achievable in the respiratory tract following oral dosage were assessed for in-vitro activity against beta-lactamase-producing strains of Branhamella catarrhalis and Haemophilus influenzae. In agar-dilution studies, 8 mg amoxycillin/l was required to inhibit 45 strains of beta-lactamase-producing B. catarrhalis, whereas all the strains were inhibited by 0.5 mg amoxycillin/l in the presence of 0.01 mg clavulanic acid/l. Similarly, 0.1 mg amoxycillin plus 0.05 mg clavulanic acid/l were bactericidal against beta-lactamase-producing strain of B. catarrhalis and prevented regrowth within 24 h. In tests against 43 beta-lactamase-producing strains of H. influenzae, concentrations of up to 128 mg amoxycillin/l were required for inhibition, whereas 32 strains (75%) were fully sensitive to amoxycillin (MIC 0.5 mg/l) in the presence of 0.12 mg clavulanic acid/l. These concentrations of amoxycillin/clavulanic acid were also bactericidal for a beta-lactamase-producing strain of H. influenzae. The study therefore showed that amoxycillin/clavulanic acid, at concentrations similar to those likely to be achieved in the respiratory tract following oral dosage, was bactericidal in vitro for beta-lactamase-producing isolates of B.catarrhalis and H. influenzae.