Activity of cefotaxime-aminoglycoside combinations against aminoglycoside-resistant Pseudomonas

Murray, Patrick R.

doi:10.1128/aac.17.3.474

Cited by 13 publications

(4 citation statements)

References 10 publications

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“…In a killing-curve study by Klastersky et al [13], the combination cefazolin and ami kacin acted synergistically against 75% of the investigated Klebsiella strains. In checkerboard studies of P. aeruginosa, ce fotaxime and gentamicin acted synergisti cally against approximately 60% of the strains [25,26]. This was in accordance with the 50% synergistic activity observed in our study when optimal concentrations of cefotaxime and netilmicin were tested.…”

Section: Discussionsupporting

confidence: 75%

Time-Kill Studies and Synergy Testing of Broad-Spectrum Antibiotics against Blood Culture Isolates

Arpi

1988

Chemotherapy

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Time-kill studies and synergy testing were performed with blood culture isolates from 80 patients with septicemia. Ten isolates each of Escherichia coli, Proteus mirabilis, indole-positive Proteus, Klebsiella pneumoniae, Enterobacter cloacae, Pseu-domonas aeruginosa, Staphylococcus aureus, and coagulase-negative staphylococci were included. The isolates were tested against netilmicin, piperacillin, cefoxitin, cefuroxime, and cefotaxime, alone and in different combinations. Cefotaxime was the most active agent against Enterobacteriaceae, whereas netilmicin was the most active agent against P. aeruginosa and staphylococci. The most active antibiotic combinations were netilmicin-cefotaxime and netilmicin-piperacillin, where a synergistic activity was observed in 68 and 61%, respectively. The highest synergistic activity was against Enterobacteria-ceae, but the netilmicin-cefotaxime combination also acted synergistically against more than half of the S. aureus isolates. A relatively low synergistic activity was noted against P. aeruginosa. No case of antagonism was observed. Subinhibitory concentrations of netilmicin, in combination with a ≥ MIC concentration of one of the tested β-lactam antibiotics, significantly improved the killing of the isolates. Netilmicin exerted a more rapid and pronounced bacterial reduction than the β-lactam antibiotics tested.

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Section: Discussionsupporting

confidence: 75%

Time-Kill Studies and Synergy Testing of Broad-Spectrum Antibiotics against Blood Culture Isolates

Arpi

1988

Chemotherapy

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“…Due to the serious side effects of treatment with CHL, such as aplastic anemia [ 13 ], in the current study, we went on to evaluate the interaction between CTX and GEN, which inhibits protein synthesis by binding to the 30S ribosomal subunit instead of the 50S subunit as CHL does. This antibiotic was chosen instead of CHL because combination treatment between ß-lactams and aminoglycosides is well known and due to the fact that GEN is more relevant in human medicine [ 50 , 51 , 52 , 53 ]. Our results showed that the MIC of CTX could be reduced from 256 to 2 mg/L by the addition of just 0.5 mg/L GEN in E. coli MG1655 expressing bla CTX-M-1 .…”

Section: Discussionmentioning

confidence: 99%

Uncovering the Important Genetic Factors for Growth during Cefotaxime-Gentamicin Combination Treatment in blaCTX-M-1 Encoding Escherichia coli

et al. 2023

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Due to the rapid spread of CTX-M type ESBLs, the rate of resistance to third-generation cephalosporin has increased among Gram-negative bacteria, especially in Escherichia coli, and there is a need to find ways to re-sensitize ESBL E. coli to cephalosporin treatment. A previous study showed that genes involved in protein synthesis were significantly up-regulated in the presence of subinhibitory concentration of cefotaxime (CTX) in a CTX-M-1-producing E. coli. In this study, the interaction between CTX and gentamicin (GEN), targeting protein synthesis, was evaluated in MG1655/pTF2, and the MIC of CTX was strongly reduced (128-fold) in the presence of this combnation therapy. Since the underlying mechanism behind this synergy is not known, we constructed a saturated transposon mutant library in MG1655/pTF2::blaCTX-M-1 containing 315,925 unique transposon insertions to measure mutant depletion upon exposure to CTX, GEN, and combination treatment of CTX and GEN by Transposon Directed Insertion-site Sequencing (TraDIS). We identified 57 genes that were depleted (log2FC ≤ −2 and with q.value ≤ 0.01) during exposure to CTX, 18 for GEN, and 31 for combination treatment of CTX and GEN. For validation, we deleted eight genes that were either uniquely identified in combination treatment, overlapped with monotherapy of GEN, or were shared between combination treatment and monotherapy with CTX and GEN. Of these genes, we found that the inactivation of dnaK, mnmA, rsgA, and ybeD increased the efficacy of both CTX and GEN treatment, the inactivation of cpxR and yafN increased the efficacy of only CTX, and the inactivation of mnmA, rsgA, and ybeD resulted in increased synergy between CTX and GEN. Thus, the study points to putative targets for helper drugs that can restore susceptibility to these important drugs, and it indicates that genes involved in protein synthesis are essential for the synergy between these two drugs. In summary, the study identified mutants that sensitize ESBL-producing E. coli to CTX and a combination of CTX and GEN, and it increased our understanding of the mechanism behind synergy between β-lactam and aminoglycoside drugs. This forms a framework for developing new strategies to combat infections caused by resistant bacteria.

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“…Cephalosporins and penicillins are used frequently in combination with aminoglycoside antibiotics in the treatment of gram-negative rod bacteremia (4), and the synergistic activity obtained with these combinations has been related to improved outcome in severely neutropenic bacteremic patients (6). Also, in vitro studies have demonstrated synergism between cefotaxime and aminoglycosides against aminoglycoside-resistant strains of P. aeruginosa (8) Serum levels of moxalactam and cefotaxime were similar when the drug was administered alone or in combination with tobramycin. Cefotaxime levels at 1 h were 7.77 ± 1.2 tig/ml alone and 8.97 ± 1.5 tg/ml in combination.…”

Section: Moxalactam (1-oxa-/l-lactam) and Cefotaximementioning

confidence: 99%

Serum Bactericidal Activity of Moxalactam and Cefotaxime With and Without Tobramycin Against Pseudomonas aeruginosa and Staphylococcus aureus

Lagast

Zinner

Klastersky

1981

Antimicrob Agents Chemother

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Serum bactericidal activity was determined against 10 strains each of Pseudomonas aeruginosa and Staphylococcus aureus in serum from volunteers 1 and 6 h after intravenous infusion of cefotaxime, tobramycin, and the combination; or of moxalactam, tobramycin, and the combination. High serum bactericidal activity against P. aeruginosa was found significantly more frequently with moxalactam plus tobramycin than with cefotaxime, moxalactam, and tobramycin alone or with cefotaxime plus tobramycin.Moxalactam (1-oxa-/l-lactam) and cefotaxime are new antibiotics with increased activity against Enterobacteriaceae relative to older penicillins and cephalosporins (2,9,(12)(13)(14)(15). In addition, both drugs have in vitro activity against Pseudomonas aeruginosa (2,9,12,13,15). Both of these agents have in vitro activity against Staphylococcus aureus, but this activity may not be as great as that of older antibiotics of similar composition (2,9,12,15). Cephalosporins and penicillins are used frequently in combination with aminoglycoside antibiotics in the treatment of gram-negative rod bacteremia (4), and the synergistic activity obtained with these combinations has been related to improved outcome in severely neutropenic bacteremic patients (6)

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Activity of cefotaxime-aminoglycoside combinations against aminoglycoside-resistant Pseudomonas

Cited by 13 publications

References 10 publications

Time-Kill Studies and Synergy Testing of Broad-Spectrum Antibiotics against Blood Culture Isolates

Time-Kill Studies and Synergy Testing of Broad-Spectrum Antibiotics against Blood Culture Isolates

Uncovering the Important Genetic Factors for Growth during Cefotaxime-Gentamicin Combination Treatment in blaCTX-M-1 Encoding Escherichia coli

Serum Bactericidal Activity of Moxalactam and Cefotaxime With and Without Tobramycin Against Pseudomonas aeruginosa and Staphylococcus aureus

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