Randomized trial of empiric antibiotic therapy with ticarcillin in combination with gentamicin, amikacin or netilmicin in febrile patients with granulocytopenia and cancer

The in vitro synergistic activities of moxalactam, cefoperazone, or cefotaxime in combination with amikacin or piperacillin were compared against aminoglycoside-susceptible and aminoglycoside-resistant isolates of Pseudomonas aeruginosa and Serratia marcescens by the checkerboard agar dilution method. All antimicrobial combinations demonstrated some synergy, and no antagonism was observed. Moxalactam plus amikacin and piperacillin plus amikacin were most frequently synergistic (two-thirds of the isolates inhibited synergistically by each combination), whereas combinations of moxalactam, cefotaxime, or cefoperazone with piperacillin were synergistic against only 18 to 25% of the isolates. Moxalactam plus amikacin was the combination most often synergistic for amikacinsusceptible P. aeruginosa, and piperacillin plus amikacin was the combination most frequently synergistic for amikacin-resistant P. aeruginosa and amikacinsusceptible S. marcescens. These results demonstrate frequent in vitro synergistic activity between the new beta-lactam agents and amikacin (especially moxalactam or piperacillin with amikacin), but comparative clinical trials are needed to establish the relative efficacy and toxicity of these combinations.Although well-controlled, definitive clinical studies are lacking, several animal and human studies suggest that Pseudomonas aeruginosa and Serratia marcescens infections may be favorably influenced by treatment with synergistic antimicrobial combinations consisting of an aminoglycoside plus carbenicillin or ticarcillin (1,9,16,17,22). However, the usefulness of these specific combinations has been recently curtailed by the increasing resistance of P. aeruginosa and S. marcescens to carbenicillin and ticarcillin and even to some of the aminoglycosides (18,20,21). Furthermore, a history of a severe allergic reaction to penicillin usually prohibits the use of carbenicillin or ticarcillin.Moxalactam, cefoperazone, and cefotaxime are three new beta-lactam antimicrobial agents with remarkably wide spectra of in vitro antibacterial activity that include most P. aeruginosa and S. marcescens isolates as well as Escherichia coli, Klebsiella spp., Enterobacter spp., Proteus mirabilis, indole-positive Proteus spp., and Bacteroides fragilis (10). These drugs also have inhbitory activity for many strains resistant to carbenicillin, ticarcillin, and the aminoglycosides (6,11,12). Whereas numerous previous studies have focused on the in vitro effectiveness of moxalactam, cefoperazone, and cefotaxime as single agents and their enhanced antibacterial activity over presently available beta-lactam agents, there is a relative paucity of infornation on the relative synergistic activity of these drugs with aminoglycosides or other beta-lactam agents against recent clinically significant bacterial isolates. Thus, we compared the in vitro synergistic activity of moxalactam, cefoperazone, or cefotaxime in combination with amikacin or piperacillin against aminoglycoside-susceptible and aminoglycoside-resistant P. aerugino...

Section: Resultssupporting

confidence: 63%

Comparative in vitro synergistic activity of new beta-lactam antimicrobial agents and amikacin against Pseudomonas aeruginosa and Serratia marcescens

Kurtz¹,

Winston²,

Bruckner³

et al. 1981

“…Previous reports, using criteria identical to ours, found rates of nephrotoxicity ranging from 2 to 8% with these same drugs (12,20). We have no explanation for the comparatively low rate of renal damage (1/69 = 1.4%) encountered in the present study.…”

Section: Discussionsupporting

confidence: 58%

“…These do not appear to differ significantly in efficacy or toxicity in humans (10,12,20). However, a recent study found that tobramycin was significantly less nephrotoxic than gentamicin (C. R. Smith The efficacy of a new congener, netilmicin, has been compared with that of other aminoglycosides in prospective randomized trials.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Prospective, randomized trial of netilmicin and amikacin, with emphasis on eighth-nerve toxicity

Barza¹,

Lauermann²,

Tally³

et al. 1980

The toxicity of netilmicin was compared with that of amikacin in a randomized, prospective trial in 90 adults with a variety of serious gram-negative infections. There was no instance of antibiotic-related nephrotoxicity in the group given amikacin and only one instance in the group given netilmicin. Cochlear toxicity, as measured by a change in audiogram, occurred in 4/14 (28.5%) of the amikacin recipients and 3/19 (15.8%) of the netilmicin recipients. Vestibular toxicity, as determined by a change in ice-water calorics, was noted in 3/16 (19%) of the amikacin-treated patients and 0/15 of the netilmicin-treated individuals. Despite the trend toward lesser ototoxicity with netilmicin, the differences between the drugs were not statistically significant. There was, however, a significant association between male sex and the development of ototoxicity. Although many patients could not be evaluated for efficacy, there did not appear to be any difference in the therapeutic activity of the two drugs.

“…In experimental animals the nephrotoxicity and ototoxicity of netilmicin are lower than those of the other aminoglycosides (3,6,9,11,18,20,22,25, 36 Florence, Italy, 1981), and in a large prospective randomized trial (15) the ototoxicity of netilmicin was lower than that of tobramycin (P = 0.037). In four prospective randomized studies reported so far, however, the rates of toxicity of netilmicin, gentamicin, and amikacin have been similar (2,4,10,17).Adult patients with possible or documented sepsis, urinary or biliary tract infection, or pneumonia and for whom an aminoglycoside was considered indicated by a doctor other than one of the investigators were candidates for entry into the trial. Informed consent was obtained in each case.…”

mentioning

confidence: 99%

Prospective randomized double-blind comparison of nephrotoxicity and auditory toxicity of tobramycin and netilmicin

Gatell¹,

SanMiguel²,

Araujo³

et al. 1984

Netilmicin or tobramycin was administered to 197 patients in a prospective randomized double-blind trial. Of these patients, 140 recipients of nine or more doses of netilmicin or tobramycin could be evaluated for nephrotoxicity. Fifty-five patients were able to cooperate in the administration of serial audiograms. Nephrotoxicity of similar severity developed in 7 of 73 (9.6%) recipients of tobramycin and in 7 of 67 (10.4%) recipients of netilmicin (P > 0.05). Mild or slight auditory toxicity developed in 5 of 28 (17.8%) recipients of tobramycin and in 2 of 27 (7.4%) recipients of netilmicin (P > 0.05).Toxicity is the major limiting factor in the clinical usefulness of aminoglycosides (16,26). In experimental animals the nephrotoxicity and ototoxicity of netilmicin are lower than those of the other aminoglycosides (3,6,9,11,18,20,22,25, 36 Florence, Italy, 1981), and in a large prospective randomized trial (15) the ototoxicity of netilmicin was lower than that of tobramycin (P = 0.037). In four prospective randomized studies reported so far, however, the rates of toxicity of netilmicin, gentamicin, and amikacin have been similar (2,4,10,17).Adult patients with possible or documented sepsis, urinary or biliary tract infection, or pneumonia and for whom an aminoglycoside was considered indicated by a doctor other than one of the investigators were candidates for entry into the trial. Informed consent was obtained in each case. Patients allergic to aminoglycosides or infected with an organism known to be resistant to tobramycin or netilmicin or who had received an aminoglycoside in the previous 30 days were not entered into the study. The trial was prospective and controlled. Drug assignments were random (a computer-generated table was used), and a double-blind evaluation of toxicity was performed. Serum aminoglycoside measurements and appropriate dosage changes were supervised by an nonblinded member of the investigative group. The patient and the clinical investigator (J.M.G.) responsible for the evaluation of each case did not know which aminoglycoside had been given. Antibiotic therapy other than aminoglycosides and nonantibiotic therapy were not controlled in trial protocol. The loading dose of tobramycin and netilmicin was 1.7 mg per kg of total body weight given intravenously over 20 or 30 min. Maintenance doses were initially adjusted for renal function according to a nomogram * Corresponding author.