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The aminoglycosides gentamicin, tobramycin, netilmicin and aztreonam were tested for their effects on migration inhibition factor production by mouse lymphocytes challenged by phytohemagglutinin in vitro. The three aminoglycosides were found to depress its production while aztreonam was devoid of this depression effect.
Minimal inhibitory concentrations (MIC) of micronomicin (MCR) and gentamicin (GM) against clinically isolated Pseudomonas aeruginosa F 4150 were 1.56 mcg/ml and 6.25 mcg/ml, respectively. Sisomicin, dibekacin, amikacin, netilmicin, tobramycin ribostamycin and kanamycin did not inhibit the strain at the concentrations less than 25 mcg/ml. Each aminoglycoside antibiotic was incubated in Tris-HCl buffer solutions (pH 7.8) containing cell free crude enzyme preparations obtained by sonic oscillation of intact cells of P. aeruginosa F 4150, coenzyme A and adenosine-5'-triphosphate. The residual activity at 3 hours of incubation at 37 degrees C was 88% for MCR and 33.6% for GM, while all of the other aminoglycoside antibiotics tested were completely inactivated under this condition.
A total of 23 antimicrobial drugs were examined for bactericidal activity in midstream-urine against Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Staphylococcus aureus ATCC 25923, or Streptococcus faecalis ATCC 29212 at incubation temperatures of 35, 22, and 7 degrees C, respectively. The majority of chemotherapeutic agents significantly reduced bacterial inocula within 2 h at 35 degrees C. At room temperature, most drugs required 4 h for significant killing activity to ensue. At 7 degrees C only nitrofurantoin, polymyxin B, and rifampin were significantly active within 2 to 4 h following exposure. Following prolonged (overnight) incubation at 7 degrees C, however, 10 of 23 drugs (amikacin, cefotaxime, chloramphenicol, gentamicin, nalidixic acid, netilmicin, nitrofurantoin, polymyxin B, rifampin, and vancomycin) effected reduction of bacterial colony counts of greater than or equal to 50%. On the basis of these data it is recommended that urine specimens from patients with known antibacterial chemotherapy should not be refrigerated for longer than 2 to 4 h following collection.
Analysis of 20 cases of staphylococcal septicemia, observed over 1 1/2 months in a general hospital, confirms that these infections are frequent and severe. They occurred in compromised hosts and were nosocomial infections in 2/3 of cases. An intravenous device (particularly a central venous catheter) was associated with 70% of staphylococcal septicemia. Study of bacterial susceptibility to antibiotics and clinical course leads to advocate that high risk patients with fever be initially given rifampin combined with netilmicin.
The structure of the causative agents isolated from patients with pyoinflammatory infections in 1980-1983 was analysed. It was shown that the surgical and urological infections were mainly caused by gram-negative bacteria. The other pyoinflammatory infections were mainly due to gram-positive cocci. A relatively high frequency of the strains of gram-negative bacteria, especially among Pseudomonas spp. and Enterobacter spp., resistant to aminoglycoside antibiotics, such as gentamicin, sisomycin and tobramycin with preserved sensitivity to amikacin and netilmicin in the majority of the strains was shown. Among the beta-lactam antibiotics cephotaxim and cephalotin were most active against gram-negative bacteria and staphylococci, respectively. The majority of the antibiotic resistant strains of gram-negative bacteria had analogous structures and levels of resistance to 7-12 antibiotics which might indicate the occurrence of 1-2 resistance plasmids among the clinical strains.
There are few studies of the influence of aminoglycoside antibiotics on the ribosomes of higher eukaryotic organisms. To this end, cytoplasmic ribosomes were prepared from rat liver. In vitro, poly(U)-directed ribosome protein synthesis was studied in the presence and absence of selected aminoglycosides. Misreading of poly(U) was also assessed. Consistent with earlier studies using different sources of ribosomes, paromomycin inhibited cell-free protein synthesis and caused poly(U) misreading. In contrast to the findings of other studies in cell-free ribosomes of eukaryotic organisms, netilmicin, tobramycin, and neomycin were most active in inhibiting protein synthesis, and gentamicin C2 and neomycin caused appreciable misreading. Thus the previous suggestion that a paromamine fragment (found in paromomycin) might be a structural requirement for in vitro inhibition of protein synthesis and misreading is not substantiated by the results in rat liver ribosomes. Commercial gentamicin C is a mixture of gentamicins C1, C1a, and C2. Despite nearly identical chemical structures, the three constituents displayed greatly different propensities for inducing poly(U) misreading. C2 was the most active, followed by C1a. In summary, selected aminoglycoside antibiotics caused inhibition and mistranslation of poly(U) messenger in an in vitro ribosome system prepared from rat liver. These effects were not limited to paromamine-containing aminoglycoside antibiotics. Gentamicin C2 caused much more poly(U) misreading than the other two constituents of the gentamicin C complex.
The effect of newer penicillins (azlocillin, mezlocillin, cyclacillin, and piperacillin) a 6 beta-amidinopenicillanic acid derivative (amdinocillin), and newer aminoglycosides (netilmicin and sisomicin) on the accuracy of tests for glycosuria was studied. Solutions of each of the drugs were prepared in urine in a range of clinically obtainable drug concentrations. In addition, urine solutions were prepared that contained the same drug concentrations and 0.5, 1, and 2% glucose. All solutions were tested in triplicate using the five-drop Clinitest method and two glucose oxidase methods (Diastix and Tes-Tape). Falsely elevated Clinitest readings of approximately 0.25% were obtained with the penicillins. These readings were influenced by the concentration of the penicillins and of glucose. Neither amdinocillin nor the aminoglycosides had an effect on Clinitest determinations. None of the drugs interfered with Diastix or Tes-Tape readings. Because the Clinitest-penicillin interaction is unpredictable, Clinitest results should be rechecked using one of the qualitative glucose oxidase tests when Clinitest is used as a quantitative test for glycosuria in patients receiving penicillins. All three tests studied can be used to test for glycosuria in patients receiving amdinocillin or one of the aminoglycosides.
In a series of Pseudomonas aeruginosa strains resistant to gentamicin, tobramycin, amikacin and/or netilmicin (Knothe and Krcméry, 1979), wild-type phage lysates could be prepared and two of them were studied more in detail. Both lysates were shown to mediate transfer of gentamicin, amikacin and carbenicillin resistance by direct selection. In some instances also fertility function (tra) could be demonstrated in transductants by further cycles of transfer. It could be speculated that, once such wild-type phages from resistant or toxinogenic strains are liberated into the hospital environment, they could mediate these and other properties to P. aeruginosa strains in that environment.
The in vitro susceptibility of 40 clinical isolates of Pseudomonas aeruginosa to 10 antipseudomonal antibiotics was determined. Of the strains examined, 100, 90, 85 and 80% were susceptible to netilmicin, amikacin, gentamicin and tobramycin, respectively; 93, 85 and 72% were susceptible to piperacillin, azlocillin and carbenicillin, respectively; and 93, 88 and 84% were susceptible to cefotaxime, moxalactam and cefsulodin, respectively. These data confirm that the newer antipseudomonal antimicrobial agents are more effective against Ps. aeruginosa than the older agents.
In vitro susceptibility of 338 clinical isolates of Pseudomonas aeruginosa to twelve antipseudomonal antibiotics were determined. Correlation between antibiotic resistance and serotypes was also performed. It was shown that the newer beta-lactams cefsulodin, piperacillin, azlocillin and mezlocillin had high biological activity against carbenicillin-resistant strains of P. aeruginosa. The most active aminoglycosides against gentamicin-resistant strains of P. aeruginosa were amikacin and netilmicin. Carbenicillin-resistant strains were most frequently observed among serotypes 4, 11 and NT group, and gentamicin-resistant strains among serotypes 3, 11 and NT group.
We describe the use of a solid-phase immunofluorescence method (FIAX system) for measuring drug concentrations, specifically gentamicin, in serum or plasma. Antibody to gentamicin is immobilized on a polymeric surface. This Sampler is immersed in a mixture of serum standard or unknown and a buffered solution of fluorescent-labeled gentamicin. After 30 min, the fluorescence of the specifically bound labeled gentamicin is measured with a fluorometer. The assay detects gentamicin in concentrations as low as 50 mug/L. It is specific for gentamicin, cross reactivity to some other therapeutic drugs, except netilmicin and sisomicin, being low. Results by this assay compare well with those by a radioimmunoassay (r = 0.94) and a radioenzymic assay (r = 0.95). The assay is specific, economical, simply performed, requires little pipetting, and does not involve the use of radioisotopes.
The "Autobac" apparatus permitted the rapid determination of the light-scattering index 50% (LSI50) and inhibitory concentration 50% (CI50) of eight antibiotics -- kanamycin, amikacin, lividomycin, gentamicin, tobramycin, sisomicin, netilmicin and colistin -- for the strain of Escherichia coli ATCC-25922. The results were compared with those of the reference method using an agar dilution method. The percentage of inhibition (% I) was obtained from LSI by applying the formula % I = 10(-(GIXLSI)). The growth index (GI) has an influence on the values of the rapid method. The best results were observed in the GI ranges of 1.2 to 1.7. For all the antibiotics except tobramycin and colistin, the CI50 values of the two methods were very similar. The values of LSI50 were not assimiliated to those of CI50. These three parameters had a small variability. The averages of standard deviation were 0.23 log2 for the CI50 of the reference method, 0.24 log2 for the CI50 of the rapid method and 0.32 log2 for the LSI50. The "Autobac" enables the determination of CI50 by a simpler and faster technique.
The frequency with which various bacteria are isolated from samples of hospitalized patients and the occurrence of sensitivity to antimicrobial agents in these bacteria are described. Data were collected and summarized by an electronic data processing system. Sensitivity data were obtained with the disc diffusion test carried out by the Bauer/Kirby method. E. coli and S. aureus were the most frequently isolated organisms. Pseudomonas sp. (in 90% Pseud. aeruginosa) took second place behind E. coli among gramnegative rod bacteria. As a rule more than 50% of grampositive and gramnegative bacteria were sensitive to betalactam antibiotics and broad spectrum agents. Aminocyclitols were the most potent drugs. Strains resistant to netilmicin or amikacin were only exceptionally observed. A comparison of the occurrence of sensitive bacteria from 1975 to 1980 revealed that with rare exceptions no decrease of sensitivity to standard drug occurred in E. coli, the Klebsiella-Enterobacter-Serratia group, Pseudo. aeruginosa and S. aureus.
Acquired insensitivity to the nephrotoxic effects of gentamicin develops in Fischer 344 rats after 10 to 14 days' treatment after development of histologic acute tubular necrosis in a setting of extensive histologic regeneration. To determine the relative importance of aminoglycoside exposure, necrosis, and regeneration in the induction of insensitivity, we examined the effect on gentamicin toxicity of prior non-aminoglycoside-mediated tubular necrosis, antecedent nonnecrotizing aminoglycoside exposure, and unilateral Nx-induced renal tubular hyperplasia. Pretreatment with potassium dichromate, which causes tubular necrosis in the same part of the renal cortex as gentamicin, reduced gentamicin-mediated elevation of Scr but had little effect on gentamicin-related tubular dysfunction or structural damage. Pretreatment with netilmicin, which does not cause tubular necrosis, increased the sensitivity of the kidney to gentamicin; toxicity occurred earlier and was more severe. Antecedent unilateral Nx had no demonstrable effect on susceptibility to gentamicin-associated dysfunction, but histologic renal tubular epithelial regeneration and recovery from dysfunction occurred earlier, These results suggest that necrosis and/or regeneration is the major prerequisite for development of gentamicin insensitivity and that the onset of insensitivity is temporally related to the appearance of necrosis and regeneration. However, non-aminoglycoside-mediated necrosis and regeneration fail to fully-re-create insensitivity, suggesting that exposure to gentamicin is also necessary.
Dibekacin is a new aminoglycoside derived semi-synthetically from kanamycin B. Its in vitro antibacterial activity, evaluated by the study of 43 reference strains and 1,177 clinical isolates, was found to be very similar to that of gentamicin, tobramycin, sisomicin and netilmicin on strains sensitive to these aminoglycosides; in the case of strains carrying plasmidic resistance factors, dibekacin behaves like tobramycin; it is inactivated by the same bacterial enzymes.
An enzymatic, radiochemical assay procedure for measuring serum gentamicin by use of gentamicin 3-acetyl-transferase and [acetyl-14C]acetyl-Coenzyme A is described and evaluated. The enzyme stoichiometrically and quantitatively transfers a radioactive label to the analyte during a 10-min incubation at 37 degrees C. The labeled gentamicin is then absorbed onto phosphocellulose paper discs, which are washed to remove unreacted [acetyl-14C]-acetyl-Coenzyme A and counted in a liquid scintillation counter for 1 min each. The assay detects gentamicin in concentrations as low as 0.2 mg/liter and gives a linear response to concentrations as high as 20 mg/liter. Sisomicin, a structural analog of gentamicin, is measured by the procedure, and tobramycin and netilmicin are slightly reactive. No other interferents were found among other aminoglycosides, other antibiotics, or substances endogenous to serum. Results by the new method are compared to those by radioimmunoassay and a microbiological method.
We studied the effects of furosemide on the disposition of cefazolin and gentamicin in rabbits. The following points were investigated: protein binding (PB) by ultracentrifugation in vitro; renal excretion and distribution in extravascular fluid (EF) obtained from s.c. tissue cages in vivo. Single i.m. injections of cefazolin (30 mg/kg) and gentamicin (1.5 mg/kg) alone or in combination with furosemide (0.5, 1 and 5 mg/kg) were made. After furosemide injection, blood and EF levels of gentamicin significantly decreased. Cefazolin blood levels were unchanged. Cefazolin appeared in EF earlier and at higher levels, up to 4 hr after furosemide injection, than when administered alone. Late cefazolin EF levels (8 and 12 hr) were reduced. All these effects were furosemide dose-dependent. Furosemide, in vitro, decreased cefazolin PG from 80 to 50%, whereas PB of gentamicin remained minimal (0--4%). Furosemide significantly increased the renal excretion of cefazolin and gentamicin without any effect on the glomerular filtration rate. A competitive effect of furosemide on the PB of cephradin and netilmicin was also demonstrated in vitro and in vivo. Our studies outline two kinds of interaction between furosemide and antibiotics. With protein-bound drugs, furosemide induced a competitive reduction of PB responsible for earlier EF diffusion and increased glomerular filtered load, but also induced an increased renal excretion by a tubular process. The latter was the only one induced by furosemide on unbound drugs (gentamicin).
When amikacin was administered to Fischer rats at a dose of 120 mg/kg/day for up to 14 days, renal proximal tubule cells became vacuolated, but BUN and creatinine remained normal. Renal cortical drug levels rose steadily throughout the treatment period. When, in a second trial of the same duration, the drug dose was tripled, focal proximal tubular necrosis, then regeneration, occurred and the animals became azotemic. Tissue drug concentrations peaked and began to decline during the treatment period, having reached levels more than three times higher than achieved at the lower dose. Ultrastructural changes were similar to those observed with other aminoglycosides. The results indicate that amikacin is less nephrotoxic than gentamicin and more toxin than tobramycin and netilmicin in the Fischer rat.