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PubMed1986

Surveillance of aminoglycoside resistance. European data.

The susceptibility patterns of gram-negative aerobic organisms to aminoglycosides differ widely from one European health care center to another and depend upon local antibiotic prescribing policies. Reports of the susceptibility of Pseudomonas aeruginosa to gentamicin and tobramycin have ranged from as low as 49.8 percent and 77.7 percent, respectively, in Greece, to as high as 96.6 percent and 99.2 percent, respectively, in the United Kingdom. The susceptibility of P. aeruginosa to gentamicin, tobramycin, and amikacin decreased in our hospital from 73.1 percent, 94.8 percent, and 95.6 percent, respectively, in 1982, to 43.1 percent, 70.6 percent, and 74.3 percent, respectively, in 1984. A prospective surveillance study of the susceptibility of gram-negative aerobic bacilli to four aminoglycosides (gentamicin, tobramycin, amikacin, and netilmicin) was performed over a period of 17 months. Gentamicin and tobramycin were freely used, while the use of amikacin was restricted throughout the hospital during a four-month baseline period (May through August 1984). Gentamicin and tobramycin accounted for 94 percent of the aminoglycoside use. During the following 13 months (September 1984 through September 1985), amikacin was used as the first-line aminoglycoside and accounted for more than 97 percent of the aminoglycoside usage. A total of 1,866 organisms were analyzed during the baseline period; 5,429 were analyzed during the amikacin-usage period. The overall susceptibility to gentamicin, tobramycin, amikacin, and netilmicin increased from 86.9 percent, 90.4 percent, 94.2 percent, and 88.3 percent, respectively, to 92.3 percent, 94.0 percent, 97.3 percent, and 92.3 percent, respectively. P. aeruginosa isolates had the most striking changes, with the susceptibility to gentamicin, tobramycin, amikacin, and netilmicin increasing from 43.1 percent, 70.6 percent, 74.3 percent, and 50.6 percent, respectively, during the baseline period, to 64.5 percent, 81.6 percent, 90.8 percent, and 65.1 percent, respectively, during the amikacin-usage period. The use of amikacin as a first-line aminoglycoside, while use of the other aminoglycosides was restricted, seemed to have a favorable influence on the susceptibility pattern of gram-negative aerobic isolates in our hospital.

Amikacin↗

PubMed1993

Interactions of drugs acting against Staphylococcus aureus in vitro and in a mouse model.

Two combinations of antibiotics, clindamycin with rifampicin and cloxacillin with netilmicin, were investigated for their activity against two strains of Staphylococcus aureus (a sensitive reference strain and a methicillin-resistant clinical isolate) by means of the in vitro checkerboard technique and an in vivo infected mouse model. The mouse model allowed drug interactions to be evaluated both from the changes in the number of bacteria surviving treatment and from the measured exposure to antibiotics at the site of infection. Specimens from the latter were evaluated twice (day 0 and day 2) in each experiment. The combination of cloxacillin and netilmicin exhibited a synergistic effect against the reference strain both in vitro and in vivo, whereas synergism was obtained under in vitro conditions only against the methicillin-resistant strain. The clindamycin and rifampicin combination acted synergistically or indifferently against both strains in vitro and at day 0 of the in vivo experiments. In contrast, on day 2 of infection, this combination had significantly greater bactericidal effect (synergism) compared to the combination of cloxacillin and netilmicin. These results illustrate the difficulties of interpreting in vitro results for clinical use.

Animals↗

PubMed1984

Nephrotoxic and ototoxic effects of hydroxygentamicin in cats.

Hydroxygentamicin, an aminoglycoside antibiotic, was administered subcutaneously to cats in doses up to 160 mg base/kg daily for 10 to 13 weeks. Gentamicin and a vehicle solution were tested as positive and negative control, respectively; in one test netilmicin was also included for comparative purposes. Several parameters, including serum urea nitrogen, serum creatinine, organ/body weight ratios, serum and tissue concentrations of the antibiotics, and renal pathology, were determined to ascertain the nephrotoxic potential of the three aminoglycosides. In addition, observations for the onset of ataxia and impairment of righting reflex were made during the course of the studies to compare the vestibular ototoxic effects of the three antibiotics. Although serum urea nitrogen and serum creatinine values increased markedly in those cats which eventually died or were sacrificed moribund, these parameters in survivors were slightly but not significantly higher than controls. Serum concentrations of the drugs were proportional to the doses administered, but renal concentrations were approximately two and five times as high for netilmicin and gentamicin, respectively, as they were for equivalent doses of hydroxygentamicin. The morphological changes observed in the kidney of cats given 60 mg base/kg of hydroxygentamicin were slightly less than those seen in cats administered 10 mg base/kg of gentamicin; similarly, kidney changes in cats given netilmicin were observed approximately twice as frequently as they were in those receiving equivalent doses of hydroxygentamicin. The nephrotoxic effects of aminoglycoside antibiotics were directly related to renal drug concentration and not to serum concentration, which was a function of dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminoglycosides↗

PubMedDate not supplied

Aminoglycoside ototoxicity.

The author participated in two prospective studies of patients receiving aminoglycoside antibiotics. In the first study, 54 patients received amikacin, and 54 received gentamicin. In the second study, 61 patients received gentamicin, 50 received netilmicin, and 52 received tobramycin. The studies were randomized and the investigator was blinded when evaluating auditory and vestibular toxicity and nephrotoxicity. All patients had pure tone audiometric evaluations, and two thirds of the patients had vestibular function tests consisting of an electronystagmogram performed with 30 degrees C and 44 degrees C water. Nephrotoxicity was measured by changes in serum creatinine levels. The incidence of gentamicin toxicity in the first study was 11 per cent, and it was 18 per cent in the second study. Amikacin was ototoxic 12.9 per cent of the time, whereas the incidence of tobramycin ototoxicity was 11.5 per cent, and the incidence of netilmicin ototoxicity was 2 per cent. Cases of unilateral, delayed-onset, and reversible auditory and vestibular toxicities were seen in all drug treatment groups. Nephrotoxicity was rare with amikacin usage. Gentamicin, on the other hand, produced a 18.6 per cent, tobramycin a 25 per cent, and netilmicin a 21.3 per cent rate of nephrotoxicity.

Amikacin↗

PubMed1990

Resistance of gram-negative bacilli and staphylococci from blood cultures to aminoglycoside antibiotics. Comparison of 3 in vitro investigations from Austria 1982-1988.

A total of 790 blood culture isolates was collected during 3 study periods in 1982/83, 1984/85 and 1987/88. Staphylococci were the most frequent bacteria in the first two periods (56.5% and 63%, respectively). During the last period, E. coli was the most frequent of all species (27%). Differences in the distribution of bacteria between the laboratories were considerable. In one laboratory in Vienna, coagulase-negative staphylococci dominated in all 3 study periods (32%, 33% and 47%). Susceptibility against gentamicin, tobramycin and netilmicin (MIC less than or equal to 4 mg/l), as well as against amikacin (MIC less than or equal to 8 mg/l) were determined by a microdilution method. The resistance rates against gentamicin (G) were 25%, 21% and 25%, against tobramycin (T) 27%, 19% and 25%, against netilmicin (N) 6%, 4% and 19%, and against amikacin (A), 5%, 2% and 19%. Most resistant strains were staphylococci (G 26%-41%, T 26%-46%, N 3%-31%, A 3%-36%), whereas gram-negative bacilli were more susceptible (G 12%-14%, T 7%-11%, N 7%-9%, A 1%-7.5%). The increase of resistance against netilmicin and amikacin in staphylococci was most striking. Nearly all those strain could be attributed to one laboratory in Vienna. Most of them were coagulase-negative staphylococci. In the first study period, the most frequent pattern was resistance against gentamicin and tobramycin, whereas in the last period resistance to all 4 aminoglycosides dominated. The study demonstrates considerable local differences in antibiotic resistance. Monitoring of antibiotic resistance in collaborative studies using standardized methods should be a valuable tool in planning strategies for controlling an epidemic spread of resistance.

Amikacin↗

PubMedDate not supplied

[Aminoglycosides in patients with mucoviscidosis and pulmonary exacerbation. Comparison of once or three times daily administration].

Twenty-six patients with cystic fibrosis and pulmonary exacerbations were enrolled in a prospective randomized study to compare the efficacy of aminoglycosides (tobramycin or netilmicin) administered once daily (21 episodes, 5 with netilmicin, 16 with tobramycin) and thrice daily (23 episodes, 2 with netilmicin, 21 with tobramycin), respectively. In addition, the patients received an anti-pseudomonal beta-lactam antibiotic. In the single-dose group the total daily dosage was 4.97 +/- 1.12 mg/kg (total dosage per exacerbation: 74.55 mg/kg), compared to 9.60 +/- 2.70 mg/kg in the triple-dose group (total dosage per exacerbation: 165.12 mg/kg). The mean peak and trough serum levels of the aminoglycoside were 8.31 +/- 1.76 mg/l and 0.18 +/- 0.10 mg/l, respectively in the single dose group compared to 6.12 +/- 1.30 mg/l and 0.58 +/- 0.31 mg/l in the triple dose group. Success of treatment, defined as decrease in leucocyte counts, normalization of elevated CRP-values, number of days in hospital and interval until next admission to hospital, was not different between both groups. We conclude that single daily dose of aminoglycosides was as efficacious as triple dose in our patients.

Adolescent↗

PubMed1987

Inducible expression of an aminoglycoside-acetylating enzyme in Providencia stuartii.

Strains of Providencia stuartii were collected from a chronic-care geriatric ward of a large Veteran's Administration hospital. Two strains of P. stuartii, and one of Escherichia coli isolated from the same ward, were transferred five times in the presence of gentamicin or netilmicin. At the fifth transfer the MICs of both gentamicin and netilmicin for the two P. stuartii strains had increased at least ten-fold. The MICs for the E. coli remained essentially unchanged. Enzyme assay demonstrated increased activity of an aminoglycoside-2'-acetylating enzyme in P. stuartii during the period of the transfers. Five subsequent transfers in the absence of aminoglycosides resulted in return of enzyme activity to the initial level. Neither of the P. stuartii strains tested contained any detectable plasmid DNA. The 2'-acetylating enzyme in some strains of P. stuartii can be induced to high levels of activity by exposure to gentamicin or netilmicin.

Acetyltransferases↗

PubMed1989

A comparison of double beta-lactam combinations with netilmicin/ureidopenicillin regimens in the empirical therapy of febrile neutropenic patients.

In a randomized trial ceftazidime plus piperacillin or azlocillin, and netilmicin plus piperacillin or azlocillin were used as initial empirical therapy in 202 febrile neutropenic episodes. Netilmicin plus azlocillin was the most effective combination with a clinical response rate of 81% in clinically and microbiologically documented infections compared with 63% for ceftazidime plus piperacillin. All of the episodes of Gram-negative bacteraemia treated with azlocillin responded compared with 43% of those treated with piperacillin. Gram-positive organisms accounted for 52% of all bacteriologically documented infections and 40% of the febrile episodes were treated with vancomycin for presumptive or documented Gram-positive infection. Patients treated with netilmicin had significantly more nephrotoxicity than those given the double beta-lactam combinations (14.8% vs 3.5%; P less than 0.05). However, this difference was not shown in those patients who did not receive concurrent vancomycin or amphotericin. The double beta-lactam combinations were associated with more hypokalaemia (58.2% vs. 37.7%; P less than 0.05) and more colonization with yeasts (24% vs. 10.4%; P less than 0.05) but there was no evidence that their use was associated with prolongation of neutropenia. These results indicate that ceftazidime plus a ureidopenicillin would be adequate empirical therapy in situations where the concomitant use of nephrotoxic agents precludes the use of aminoglycoside containing combinations.

Adult↗

PubMed1991

Activity of aminoglycosides against phagocytosed bacteria.

The intracellular activity of streptomycin, gentamicin, and netilmicin on Escherichia coli phagocytosed by murine peritoneal macrophages was studied using a sensitive and standardized method. Intracellular activity of streptomycin and gentamicin at therapeutic concentrations was seen after 1 h of incubation of antibiotics with macrophages containing phagocytosed bacteria, whilst for netilmicin a significant intracellular activity was observed only after 3 h exposure. The activity of these antibiotics against intraphagocytic bacteria was significantly lower than that observed against extracellular bacteria. Sub-inhibitory concentrations of streptomycin were active against intracellular E. coli. Streptomycin was also active for a phagocytosed streptomycin-resistant strain of E. coli, but this activity was eliminated when the O2-dependent killing mechanisms of macrophages were inhibited by sodium fluoride. The data demonstrate that aminoglycosides may exert a dose-dependent intraphagocytic activity against E. coli that correlates with the time of incubation of the antibiotics with infected macrophages. Streptomycin appears to be the most effective agent followed by gentamicin and the least active was netilmicin. In the case of streptomycin, the intraphagocytic activity seems to be due, at least in part, to the stimulation of O2-dependent cellular microbactericidal mechanisms.

Animals↗

PubMed1985

Correlation of aminoglycoside resistance with the KmS and Vmax/Km ratios of enzymatic modification of aminoglycosides by 2''-O-nucleotidyltransferase.

A clinical isolate, Serratia marcescens 75, was found to be susceptible to netilmicin and yet had a high level of aminoglycoside 2''-O-nucleotidyltransferase activity for netilmicin. Kinetic studies of the partially purified enzyme revealed substrate inhibition for gentamicin and tobramycin at concentrations greater than 10(-2) mM, but this was not observed for netilmicin. The MICs of the aminoglycosides tested exhibited a good inverse correlation with the Km values for the enzyme and a direct correlation with the Vmax/Km ratios of the enzyme.

Aminoglycosides↗

PubMed1987

Univariate and multivariate analyses of risk factors predisposing to auditory toxicity in patients receiving aminoglycosides.

Risk factors predisposing to auditory toxicity of aminoglycosides were analyzed from records of 187 patients enrolled in three prospective randomized trials comparing the toxicity of netilmicin, tobramycin, and amikacin. Patients were eligible if they received three or more days of therapy and at least two serial audiograms were available. The overall auditory toxicity rate was 9.6% (18 of 187). Auditory toxicity was detected in 4.4, 10.8, and 23.5% of patients given netilmicin, tobramycin, and amikacin, respectively (P = 0.05). In the univariate analysis, patients who developed auditory toxicity were significantly older (P = 0.01) and had a significantly higher (P = 0.04) percentage of trough levels of netilmicin or tobramycin above 2 mg/liter or amikacin above 5 mg/liter. In the final logistic regression model, only age was retained as independently influencing the development of auditory toxicity (P less than 0.00001). Conversely, factors that did not add significantly to the prediction of auditory toxicity were aminoglycoside serum levels, total aminoglycoside dose, duration of therapy, sex, peak temperature, presence of bacteremia, shock, liver cirrhosis, dehydration, previous otic pathology or renal failure, and development of renal toxicity. At least in certain populations, age is the most important predisposing factor for the development of auditory toxicity in patients receiving aminoglycosides.

Amikacin↗

PubMed2000

Apoptosis in renal proximal tubules of rats treated with low doses of aminoglycosides.

Kidney cortex apoptosis was studied with female Wistar rats treated for 10 days with gentamicin and netilmicin at daily doses of 10 or 20 mg/kg of body weight and amikacin or isepamicin at daily doses of 40 mg/kg. Apoptosis was detected and quantitated using cytological (methyl green-pyronine) and immunohistochemical (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) staining, in parallel with a measurement of drug-induced phospholipidosis (cortical phospholipids and phospholipiduria), cortical proliferative response ((3)H incorporation in DNA and histoautoradiography after in vivo pulse-labeling with [(3)H]thymidine), and kidney dysfunction (blood urea nitrogen and creatinine). Gentamicin induced in proximal tubules a marked apoptotic reaction which (i) was detectable after 4 days of treatment but was most conspicuous after 10 days, (ii) was dose dependent, (iii) occurred in the absence of necrosis, and (iv) was nonlinearly correlated with the proliferative response (tubular and peritubular cells). Comparative studies revealed a parallelism among the extents of phospholipidosis, apoptosis, and proliferative response for three aminoglycosides (gentamicin >> amikacin congruent with isepamicin). By contrast, netilmicin induced a marked phospholipidosis but a moderate apoptosis and proliferative response. We conclude that rats treated with gentamicin develop an apoptotic process as part of the various cortical alterations induced by this antibiotic at low doses. Netilmicin, and still more amikacin and isepamicin, appears safer in this respect. Whereas a relation between aminoglycoside-induced tubular apoptosis and cortical proliferative response seems to be established, no simple correlation with phospholipidosis can be drawn.

Amikacin↗

PubMed1984

Nephrotoxic effects of aminoglycoside treatment on renal protein reabsorption and accumulation.

To quantify the effects of gentamicin, kanamycin and netilmicin on renal protein reabsorption and accumulation, these drugs were administered to rats intraperitoneally (30 mg/kg/day) for 7, 14 or 21 days. Scanning electron microscopy of the glomerular endothelia, urinary measurements of sodium, potassium, endogenous lysozyme, N-acetyl-beta-D-glucosaminidase (NAG) as well as clearance and accumulation experiments after i.v. administration of egg-white lysozyme and measurements of inulin clearance (GFR) were done in each treatment group. Gentamicin administration decreased diameter, density and shape of endothelial fenestrae. Kanamycin and netilmicin appeared to have no effect at the dose used. All three aminoglycosides decreased GFR and increased urinary excretion of sodium and potassium. While gentamicin and kanamycin decreased the percentage reabsorption and accumulation of lysozyme after i.v. administration of egg-white lysozyme netilmicin had no effect. Daily excretion of total protein, endogenous lysozyme and NAG increased only after treatment with kanamycin and gentamicin. Thus, aminoglycosides may act as nephrotoxicants at glomerular and/or tubular level inducing impairment of renal reabsorption and accumulation of proteins.

Absorption↗

PubMed1988

Penetration of aminoglycosides in uninfected pleural exudates and in pleural empyemas.

The concentrations of gentamicin, netilmicin, and amikacin were determined after one single intravenous injection in uninfected pleural fluid after thoracotomy and in purulent pleural empyemas. The mean peak concentrations in the pleural fluid after the injection of gentamicin (1.5 mg/kg), netilmicin (2.0 mg/kg), and amikacin (7.5 mg/kg) were 2.9 +/- 0.3 mg/L, 3.7 +/- 0.8 mg/L, and 11.0 +/- 3.1 mg/L, respectively. The pleural penetration of the drugs was very high (from 80.0 to 99.1 percent). By contrast, gentamicin and netilmicin were not detectable in empyema pus; in this exudate the mean peak level of amikacin was 5.7 +/- 2.2 mg/L, with the penetration of this drug being 31.0 percent. The concentrations of parenterally administered aminoglycosides are substantially lower in empyema pus than in sterile pleural fluid. The possibility of poor pleural penetration of some aminoglycosides, as well as the presence of local conditions in pleural empyema unfavorable to the bioactivity of these drugs, must be kept in mind when treating pleural infections.

Amikacin↗

PubMedDate not supplied

Antimicrobial-induced endotoxaemia in patients with sepsis in the field of acute pyelonephritis.

BACKGROUND: In vitro results have shown that antimicrobial agents may induce the Gram-negative bacteria to release endotoxins (LPS), which in turn, could trigger the secretion of cytokines from monocytes. AIMS: To compare the effect of cefuroxime, netilmicin or ciprofloxacin on serum levels of LPS and tumour necrosis factor-alpha (TNFalpha). METHODS: Seventy-four patients with acute pyelonephritis caused by Gram-negative bacteria and signs of sepsis were randomly assigned to receive one of three intravenous regimens of cefuroxime, netilmicin or ciprofloxacin. Blood samples were collected before therapy and at specified time intervals for 96 hours after the initiation of treatment for the determination of serum levels of LPS and of TNFalpha. RESULTS: Patients treated with cefuroxime presented an early peak of LPS and of TNFalpha in serum two hours after the initiation of treatment compared to the other study groups. After that time interval, concentrations of LPS and TNFalpha were similar in all the study groups. Fever accompanied by endotoxaemia was still detected for 48 hours after the start of therapy in 36, 37.5 and 36% of patients treated with cefuroxime, netilmicin and ciprofloxacin respectively. The corresponding figures for these agents at 72 hours were 28, 12.5 and 24%, respective and 12, 4.2 and 4% at 96 hours (P value not significant). CONCLUSIONS: With the exception of an early peak in the serum levels of LPS and TNFalpha in patients treated with cefuroxime, no significant difference could be detected amongst the study groups as far as their effect on serum levels of LPS and TNFalpha were concerned. This suggests that these three antimicrobial agents may be administered safely at the early stages of sepsis.

Acute Disease↗

PubMed1990

Post-antibiotic effect of isepamicin compared to that of other aminoglycosides.

Isepamicin is a new aminoglycoside drug derived from gentamicin, which is more stable than other aminoglycosides to inactivating enzymes and experimentally is less nephrotoxic than gentamicin or amikacin. In this work a comparative study was carried out on the antibacterial activity (MIC and lethality curves) and the post-antibiotic effect (PAE) of different concentrations of isepamicin, netilmicin and gentamicin on pure cultures of S. aureus and E. coli. The MIC and curves of lethality were determined by conventional methods. The PAE was determined after exposure of the bacterial culture to the antimicrobial one for 1 h at 37 degrees C in a bath with stirring. Elimination of the drug was made by the dilution method. Isepamicin was found to have a MIC four times greater than netilmicin and gentamicin. Its activity over time was similar to that exhibited by other aminoglycosides. At concentrations higher than the MIC, a bactericidal effect was found with the three antibiotics, although isepamicin produced it at lower concentrations. The post-antibiotic effect induced by isepamicin, the same as that of netilmicin and gentamicin, was extensive and depended on the concentration and the strain used. Isepamicin shows antibiotic activity over time and a PAE similar to the other aminoglycosides tested but, unlike them, it has a faster activity, less toxicity and better resistance to inactivating enzymes. For this reason it makes a considerable contribution to antibacterial therapies in severe conditions, including immunodepressed patients who require long-term treatment.

Anti-Bacterial Agents↗

PubMed1989

[Microbiological findings of 97 cases of acute pyelonephritis].

To optimize the therapeutic approach to acute pyelonephritis (PNA), the medical records of 89 patients (73 women and 16 men) hospitalized with diagnosis of PNA between January 1984 and 1987 have been studied. According to routine bacteriological urinalysis, gram-negatives were found in more than 92% (E. coli in 79%, Proteus in 6%). Gram-positives were found in only 8%. The gram-negatives (n = 82) showed resistance to amoxicillin in 36%, to amoxicillin/clavulanic acid in 17%, to cotrimoxazole in 18%, and to ceftriaxone in 1%. No resistance to netilmicin or norfloxacin was found. These results justify treatment with norfloxacin or ceftriaxone instead of amoxicillin, amoxicillin/clavulanic acid or cotrimoxazole for gram-negatives. Among the 7 cases with gram-positives, resistance was found to amoxicillin/clavulanic acid, cotrimoxazole and also netilmicin, and to norfloxacin, ceftriaxone and amoxicillin. Therefore, an initial therapy using the association amoxicillin-netilmicin is recommended in PNA.

Acute Disease↗

PubMed1987

Antistaphylococcal activity of teicoplanin in association with other antibiotics.

The in vitro activity of antibiotic combination of teicoplanin and gentamicin (or netilmicin) and teicoplanin and cephalotin on Staphylococcus aureus was evaluated using the checkerboard method and time-kill curves. With few exceptions neither antagonism nor synergism was seen for the combination of teicoplanin and aminoglycosides using the checkerboard method. Using time-kill curves synergism was often found for the combination of teicoplanin and netilmicin (even at sub-minimal inhibitory concentrations of netilmicin) and for the combination of teicoplanin and cephalotin. No antagonistic interactions occurred.

Anti-Bacterial Agents↗