In vitro and in vivo studies of three antibiotic combinations against gram-negative bacteria and Staphylococcus aureus

The inhibitory and bactericidal activities of carbenicillin, ticarcillin, moxalactam, cefoperazone, azlocillin, piperacillin, ceftazidime, and three aminoglycosides, alone and in various combinations, were determined against 60 isolates of Pseudomonas aeruginosa from the sputum of patients with cystic fibrosis. Ceftazidime was the most active ,B-lactam, with minimum inhibitory and bactericidal concentrations for 90o of isolates of 4 ,ug/ml. Moxalactam was the least active of the new -lactams, with activity equivalent to that of carbenicillin; each had a minimum inhibitory concentration for 90% of isolates of 64 ,ug/ml and a minimum bactericidal concentration for 90% of isolates of 128 p.g/ml. Of the recently introduced 3-lactam derivatives, azlocillin, cefoperazone, ceftazidime, moxalactam, and piperacillin have a higher order of activity than their predecessors against not only the Enterobacteriaceae but also against Pseudomonas aeruginosa (2,10,13,15,18). Thus, they might be useful in the treatment ofP. aeruginosa pulmonary infections which are currently difficult to manage in patients with cystic fibrosis (CF). This possibility led to the current study of the activities of these new 3-lactams, alone and in combination with each other or gentamicin, tobramycin, and amikacin, against 60 isolates of P. aeruginosa from the sputum of patients with CF. MATERIALS AND METHODSA total of 60 isolates of P. aeruginosa, including mucoid and nonmucoid strains, was identified by standard microbiological methods. The organisms were then stored on tryptic soy agar slants and were checked for purity and subcultured monthly.Moxalactam (Eli Lilly & Co.), piperacillin (Lederle Laboratories), carbenicillin (Roerig-Pfizer Co.), azlocillin (Delbay Research Corp.), ticarcillin (Beecham Laboratories), cefoperazone (Pfizer Inc.), ceftazidime (Glaxo Research Group), gentamicin (Schering Corp.), tobramycin (Eli Lilly), and amikacin (Bristol Laboratories) were furnished as dry powders. Stock solutions were prepared from these powders and were used immediately or stored at -70°C for no longer than 2 weeks.Minimum inhibitory concentrations (MICs) were determined by microbroth dilution, and combination studies were done by microbroth checkerboard methods. Mueller-Hinton broth was used for all determinations. Mueller-Hinton broth was adjusted to optimal calcium and magnesium concentrations and a pH of 7.2 to 7.4 (6). The preparation and inoculation of microbroth plates were accomplished with the MIC-2000 system (Dynatech Corp.). Plates were used immediately or stored at -70°C for no longer than 2 weeks. Microbroth plates received an inoculum consisting of a 10' dilution of a log-phase culture adjusted to the density of a 0.

Section: Discussionsupporting

confidence: 81%

Activities of various beta-lactams and aminoglycosides, alone and in combination, against isolates of Pseudomonas aeruginosa from patients with cystic fibrosis

Scribner¹,

Marks²,

Weber³

et al. 1982

“…MICs for the various species were similar to those previously reported (4,14) and fit into the readily definable categories shown. The spectrum of azlocillin was complemented by the …”

supporting

confidence: 72%

“…Antagonism with azlocillin-cefotaxime was observed with 11% of the Enterobacteriaceae. [10][11][12]14). Although antagonism was not observed in the present study, it has been occasionally observed with both types of combinations against Enterobacteriaceae and P. aeruginosa (3,5,6,8,11,14).…”

mentioning

confidence: 38%

“…There were no instances of antagonism. In a similar study in which a different medium and a lower inoculum were used (14), azlocillincefotaxime and azlocillin-amikacin combinations also showed varying frequencies and degrees of synergy against Enterobacteriaceae, P. aeruginosa, and S. aureus. Antagonism with azlocillin-cefotaxime was observed with 11% of the Enterobacteriaceae.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Comparative in vitro activities of azlocillin-cefotaxime and azlocillin-tobramycin combinations against blood and multi-drug resistant bacterial isolates

Fass¹

1982

The in vitro activities of azlocillin and cefotaxime in combination and of azlocillin and tobramycin in combination against 100 blood isolates and 50 multidrug-resistant isolates were compared. With both combinations, antibacterial spectrums were complementary. Although synergy against individual strains was infrequently observed (except for azlocillin-cefotaxime against Streptococcus faecalis and azlocillin-tobramycin against Pseudomonas aeruginosa), 97% of blood isolates and 76% of multidrug-resistant isolates were susceptible to azlocillin-cefotaxime, and 94% of blood isolates and 36% of multidrug-resistant isolates were susceptible to azlocillin-tobramycin.Penicillin-aminoglycoside and cephalosporinaminoglycoside antibiotic combinations have broad antibacterial spectrums, are frequently synergistic in vitro, and are commonly used to treat a variety of serious bacterial infections (9). To avoid aminoglycoside toxicity, penicillincephalosporin combinations have also been used, but results using early derivatives have not been optimal (2). In recent years, new penicillins and cephalosporins which have greater potencies and spectrums of activity than their prototypes have been developed (4, 7). Therefore, a reexamination of the potential for using penicillin-cephalosporin combinations as alternatives to 3-lactam-aminoglycoside combinations for treating certain types of infections seems appropriate.In this study, we compared the in vitro activity of azlocillin (a new antipseudomonal penicillin) and cefotaxime (a third generation of cephalosporin) in combination with the activity of azlocillin and tobramycin (an aminoglycoside) (Difco Laboratories, Detroit, Mich.) and an inoculum size of approximately 2 x 105 colony-forming units per ml were used (6). Antibiotics were considered synergistic when there was a fourfold or greater reduction in MICs of both drugs in a combination compared with MICs of individual drugs, antagonistic when there was a fourfold or greater increase in MICs of both drugs or when the addition of an inactive antibiotic to an active antibiotic increased the MIC of the latter by fourfold or more, and indifferent when the results were intermediate. Results were considered indeterminate if the endpoints were not in the range of concentrations tested (0.25 to 256 ,ug/ml for azlocillin and 0.25 to 16 ,ug/ml for cefotaxime and tobramycin).

“…By the commonly used fractional inhibitory concentration index of .2.0 for antagonistic definition, the three moxalactam-amikacin studies show antagonism (10 (2,13,15,20). Moreover, synergy has proven to be valuable for the treatment of some infected patient populations, especially those with leukopenia and compromised immune mechanisms (12,20). It also seems critical to select the antimicrobial agents that are compatible in vitro and in vivo.…”

Section: Resultsmentioning

confidence: 99%

Antimicrobial activity of amikacin combinations against Enterobacteriaceae moderately susceptible to third-generation cephalosporins

Jones¹,

Packer²

1982

Enterobacteriaceae strains having elevated minimal inhibitory concentrations (.2.0 to s32 ,ug/ml) of cefoperazone, cefotaxime, ceftazidime, and moxalactam were synergistically inhibited by amikacin combinations (54.1 to 69.6% occurrence). Indifference was rare (8.1% for moxalactam), and true antagonistic interactions were not observed. Strains resistant or susceptible to these new cephalosporins were also synergistically inhibited by the addition of amikacin, reducing resistant cephalosporin minimal inhibitory concentrations to clinically achievable levels.Amikacin has been recognized as the currently available aminoglycoside most refractory to bacterial enzyme inactivation (18). This stability has generally limited the use of amikacin to those clinical bacterial strains resistant to kanamycin, gentamicin, and tobramycin by enzyme plasmid-mediated mechanisms. Similarly, the recently introduced third-generation cephalosporins have substantial stability to bacterial plactamases and a potent antimicrobial activity (2, 3, 6-9, 15, 16). The bacteria most likely to harbor the higher minimal inhibitory concentrations (MICs) for these new ,B-lactams are the nonfermentative bacilli and the serogroup D Streptococcus spp.; however, a few strains of Enterobacteriaceae may have MICs of 2.0 to 32 ,ug/ml (3,(7)(8)(9). These latter organisms represent a very different population of enteric bacilli only moderately susceptible (MS) to these highly active new drugs. Very few Enterobacteriaceae are currently considered resistant (MICs, .64 ,g/ml) to cefoperazone,' cefotaxime, ceftazidime, or moxalactam.To determine the possibility of using antimicrobial combinations to treat infections caused by these MS strains of Enterobacteriaceae (cefoperazone, cefotaxime, ceftazidime, or moxalactam MICs, 2.0 to 32 ,ug/ml), we screened over 6,000 organisms to find strains having elevated MICs as described above. These recent clinical isolates from The Cleveland Clinic Foundation (Cleveland, Ohio), St. Francis Hospital (Wichita, Kans.), St. Vincent Hospital and Medical Center (Portland, Oreg.), and Northwestern Memorial Hospital (Chicago, Ill.) were collected and then retested for their susceptibility to the new ,-lactams singly and in combination with amikacin. Synergy analysis was determined by the checkerboard broth dilution technique, confirmed by a limited number of bactericidal concentration isobolograms and kill curves. Some additional organisms were tested, including several with resistance to one or more of the five broad-spectrum drugs to detect their possible conversion from resistantto-susceptible MIC results by the addition of another antimicrobial agent.MATERALS AND METHODS Antibiotics. The broad-spectrum drugs utilized in all phases of this study were supplied by the following manufacturers: amikacin, Bristol Laboratories, Syracuse, N.Y.; cefoperazone, Pfizer Inc., New York, N.Y.; cefotaxime, Hoechst-Roussel Pharmaceuticals Inc., Somerville, N.J.; ceftazidime, Glaxo Inc., Research Triangle Park, N.C.; moxalactam, Eli Lilly & Co., ...