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Comparative nephrotoxicity of aminoglycoside antibiotics in rats.

Netilmicin, gentamicin, tobramycin, amikacin, kanamycin, streptomycin, and sisomicin were given daily for 15 days to groups of rats at three dosage levels corresponding to 10, 15, or 25 times the dose recommended for humans on a weight basis. Decreased urinary osmolality and increased urinary excretion of protein and beta-N-acetyl hexosaminidase were dose-related features of nephrotoxicity. Decreased tubular resorption of glucose and phosphate were observed with the most toxic regimens after extensive renal damage had occurred. All aminoglycosides accumulated in renal tissue; however, the concentration of drug in the renal cortex at the time the rats were killed was not useful for the prediction of renal impairment. Streptomycin and netilmicin exhibited a flat dose-reponse curve with respect to histological damage, as compared with the curves for the other drugs. Results of studies of creatinine clearance and examination of renal tissue suggested the following order of increasing toxicity of the treatment regimens: (1) 0.9% NaCl and uninjected controls; (2) streptomycin; (3) netilmicin; (4) tobramycin; (5) sisomicin, amikacin, and kanamycin; and (6) gentamicin.

Amikacin↗

The comparative activity of eleven aminocyclitol antibiotics against 773 aerobic gram-negative rods and staphylococci isolated from infected hospitalized patients.

The minimum inhibitory concentrations (MICs) of 11 aminocyclitol antibiotics were determined for 773 recent clinical isolates from infected hospital patients, most of whom were immunocompromised. There was a bias towards aminoglycoside-resistant organisms, and 21% of Pseudomonas aeruginosa isolates were resistant to gentamicin. The antibiotics included the natural agents gentamicin, tobramycin, sissomicin and kanamycin and the semi-synthetic compounds amikacin, netilmicin and dibekacin with some newer agents, including O-demethyl fortimicin, Hapa gentamicin B and 5-epi-sissomicin, not available commercially. Tobramycin, sissomicin and gentamicin had similar spectra with tobramycin more active against Ps. aeruginosa, sissomicin more active against proteus and gentamicin more active against serratia. The differences in spectrum between amikacin and netilmicin were marginal, reflecting the relatively low prevalence of acetyltransferase-producing organisms in our collection. Hapa-gentamicin B was the most active aminoglycoside against staphylococci and indole-positive proteus, netilmicin against Escherichia coli and 5-epi-sissomicin against Ps. aeruginosa. Overall 5-epi-sissomicin was the most active aminoglycoside tested. Both Hapa-gentamicin B and 5-epi-sissomicin have potentially valuable antibacterial spectra which merit clinical studies.

Anti-Bacterial Agents↗

In-vitro susceptibility of 1982 respiratory tract pathogens and 1921 urinary tract pathogens against 19 antimicrobial agents: a Canadian multicentre study. Canadian Antimicrobial Study Group.

A total of 3903 pathogens from 48 Canadian medical centres were tested against 19 antimicrobial agents. Five agents showed activity against > or = 90% of all 1982 respiratory tract pathogens tested (ciprofloxacin, 90%; cefoperazone, 91%; ticarcillin/clavulanate, 92%; ceftazidime and imipenem, 93% each). Nine agents had > or = 90% activity against Enterobacteriaceae from respiratory tract infection (cefotaxime and ticarcillin/clavulanate, 90% each; aztreonam, ceftizoxime and ceftriaxone, 91% each; ceftazidime, 93%; ciprofloxacin, 97%; imipenem and netilmicin, 98% each). Similarly, five agents had activity against > or = 90% of all 1921 urinary tract pathogens tested (ciprofloxacin and ticarcillin/clavulanate, 90% each; cefoperazone and netilmicin, 91% each; imipenem, 99%). Nine agents had > or = 95% activity against Enterobacteriaceae from urinary tract infection (ciprofloxacin, 95%; cefotetan, 97%; aztreonam, cefotaxime, ceftazidime, ceftizoxime, ceftriaxone and netilmicin, 98% each; imipenem, 99%). Seventeen agents had activity against > or = 95% of Staphylococcus aureus strains. Susceptibility of Pseudomonas aeruginosa isolates ranged from 2% to 91%.

Acinetobacter↗

Phenotypic and genotypic aminoglycoside resistance in blood culture isolates of coagulase-negative staphylococci from a single neonatal intensive care unit, 1989-2000.

OBJECTIVES: To investigate the prevalence of aminoglycoside resistance and genes encoding aminoglycoside-modifying enzymes (AME) in blood culture isolates of coagulase-negative staphylococci (CoNS) from neonates. MATERIALS AND METHODS: A total of 180 isolates from 148 patients collected in a single neonatal unit over a 12 year period were examined for susceptibility to gentamicin, tobramycin, netilmicin, amikacin and arbekacin by Etest and/or disc diffusion. AME genes were detected by PCR. RESULTS: The overall non-susceptibility rates to gentamicin, tobramycin, netilmicin, amikacin and arbekacin were 66%, 68%, 52%, 38% and 1%, respectively. Gentamicin non-susceptibility rates were 4% and 91% in methicillin-susceptible and -resistant isolates, respectively. aac(6')-Ie-aph(2'')-Ia, aph(3')-IIIa and/or ant(4')-Ia were encountered in 125 (69%), 1 (0.5%) and 30 (16.6%) isolates, respectively. Forty-six (26%) isolates negative for AME genes were susceptible to all aminoglycosides. In contrast, 115 (92%), 91 (73%) and 66 (53%) of aac(6')-Ie-aph(2'')-Ia positive isolates were non-susceptible to gentamicin, netilmicin and amikacin, respectively. Only one isolate showed arbekacin resistance. However, aac(6')-Ie-aph(2'')-Ia positive isolates and isolates with gentamicin MIC > or =128 mg/L displayed a significant reduction in arbekacin inhibition zones. CONCLUSIONS: A high prevalence of aminoglycoside resistance was detected and associated with methicillin resistance. Discrepancies between phenotypic and genetic detection of aminoglycoside resistance were discerned. Gentamicin was the preferred substrate for phenotypic detection of aac(6')-Ie-aph(2'')-Ia. Arbekacin showed favourable antibacterial activity even in aac(6')-Ie-aph(2'')-Ia-positive isolates. We suggest including arbekacin in future clinical trials of empirical treatment of late onset neonatal sepsis.

Aminoglycosides↗

Therapeutic aminoglycoside monitoring in renal failure patients.

In patients with normal renal function, defined peak (5-10 mg/L) and trough levels (less than 2 mg/L) for gentamicin, tobramicin, and netilmicin are considered therapeutic. Netilmicin peak and trough levels were investigated in 50 patients requiring hemodialysis due to acute (70%) or permanent (30%) renal failure. Netilmicin was given at a dosage interval of 24 h, with a loading dose on the first day (1.5 mg/kg) and a reduced daily maintenance dose (0.5 mg/kg) supplemented to the posthemodialysis dosage (1.3 mg/kg) after each hemodialysis. As compared with studies on patients not requiring hemodialysis, mortality (44%) was higher, mainly due to uncontrolled infection, whereas ototoxicity (17%) was not. Peak (5.9 +/- 1.7 mg/L) and trough plasma levels (3.0 +/- 0.9 mg/L) were significantly lower in patients who did not respond and died than were peak (8.2 +/- 2.5 mg/L) and trough (3.8 +/- 1.2 mg/L) levels in patients responding to aminoglycoside treatment. In renal failure patients, there is obviously not only the risk of overdosing and toxic side effects but also the risk of insufficient bactericidal effect as a result of underdosing. Consequently, by use of an aminoglycoside dosage similar to the present schedule, peak levels (5-10 mg/L) as desired in normal subjects but trough levels (2.5-5 mg/L) that are considerably higher than in normal subjects should be the target concentrations for patients with advanced renal failure.

Acute Kidney Injury↗

The patterns and transmissibility of antibiotic resistance among clinical strains of Pseudomonas aeruginosa.

Four hundred and ninety-eight predominantly pyocin-type 10 clinical strains of Pseudomonas aeruginosa were analyzed for resistance to carbenicillin, cefoperazone, cefotaxime, ceftazidime, gentamicin, amikacin and netilmicin. Based on NCCLS-recommended MIC breakpoints, 245 strains were found to be resistant, of which 41.6% were resistant to carbenicillin, 38% to gentamicin, 37.8% to netilmicin, 26.3% to cefoperazone, 17.9% to cefotaxime, 0.6% to amikacin and none to ceftazidime. Quadruple resistance to carbenicillin, cefoperazone, gentamicin and netilmicin was the most frequent pattern observed. Resistance to older antibiotics (kanamycin, streptomycin and tetracycline) and to mercuric chloride were also common. Conjugation experiments suggested that self-transmissible and non-transmissible plasmids occurred in at least 66 strains.

Aminoglycosides↗

Activity of newer aminoglycosides and carbenicillin, alone and in combination, against gentamicin-resistant Pseudomonas aeruginosa.

The in vitro activity of the aminoglycoside antibiotics tobramycin, sisomicin, amikacin, gentamicin, and netilmicin (SCH 20569) were compared against 26 gentamicin-resistant isolates of Pseudomonas aeruginosa cultured from hospitalized children. Tobramycin had the greatest activity on a weight basis, followed by sisomicin, gentamicin, amikacin, and netilmicin. All isolates were resistant to achievable concentrations of netilmicin and gentamicin, but 23% were inhibited by achievable concentrations of tobramycin, 8% by amikacin, and 4% by sisomicin. The combinations carbenicillin/tobramycin, carbenicillin/sisomicin, and carbenicillin/amikacin were synergistic for 92% of strains; antagonism was not encountered. These in vitro results suggest that tobramycin, sisomicin, or amikacin in combination with carbenicillin would be the safest initial regimen in the therapy of gentamicin-resistant Pseudomonas infections pending susceptibility studies.

Amikacin↗

Isolation, characterization, and cloning of a plasmid-borne gene encoding a phosphotransferase that confers high-level amikacin resistance in enteric bacilli.

Clinical isolates of Klebsiella pneumoniae and Serratia marcescens at a hospital that had used amikacin as its principal aminoglycoside for the preceding 42 months demonstrated high-level resistance to amikacin (greater than or equal to 256 micrograms/ml), kanamycin (greater than or equal to 256 micrograms/ml), gentamicin (greater than or equal to 64 micrograms/ml), netilmicin (64 micrograms/ml), and tobramycin (greater than or equal to 16 micrograms/ml). The resistant strains contained an identical 6.8-kilobase plasmid, pRPG101. Transformation of pRPG101 into Escherichia coli produced high-level resistance to amikacin (greater than or equal to 256 micrograms/ml) and kanamycin (greater than or equal to 256 micrograms/ml) but unchanged susceptibilities to gentamicin, netilmicin, and tobramycin. The clinical isolates and transformants produced a novel 3'-phosphotransferase, APH(3'), that modified amikacin and kanamycin in vitro. The location and orientation of the amk gene encoding this APH(3') were determined by analysis of insertions in pRPG101 of the defective gene fusion phage Mu dII1681 (mini-Mulac). Cells containing plasmids with insertions into amk that had the lac operon fused to the amk promoter were selected as Lac+ and amikacin susceptible. A collection of these mini-Mulac insertions was mapped by restriction enzyme analysis. This characterization of amk facilitated its cloning as a 1.8-kilobase EcoRI-Bg/I fragment of pRPG101 into the pUC19 vector. E. coli strains containing this recombinant plasmid had APH(3') activity and demonstrated high-level resistance to amikacin and kanamycin (greater than or equal to 256 micrograms/ml) but were as susceptible to gentamicin, tobramycin, and netilmicin (less than or equal to 1.0 microgram/ml) as the strains harboring the original pRPG101 plasmid.

Amikacin↗

Enhanced phagocytosis of encapsulated Escherichia coli strains after exposure to sub-MICs of antibiotics is correlated to changes of the bacterial cell surface.

The influence of five antibiotics (netilmicin, ceftriaxone, cefepime, fleroxacin, and ciprofloxacin) on capsular polysaccharide distribution and on opsonophagocytosis by human polymorphonuclear leukocytes of unencapsulated and encapsulated Escherichia coli strains was studied. Unencapsulated E. coli strains were readily opsonized in serum and easily ingested by polymorphonuclear leukocytes, and antibiotics did not further enhance the phagocytosis rates. In contrast, encapsulated bacteria were poorly opsonized in human serum, and phagocytosis was enhanced after overnight exposure to 0.5x the MICs of the antibiotics, with the exception of cefepime. Incubation of unencapsulated as well as encapsulated bacteria in complement-inactivated serum markedly reduced the bacterial uptake by polymorphonuclear leukocytes regardless of the presence of antibiotics. Slide agglutination assays, performed either with a monoclonal antibody for capsular polysaccharide or with an antiserum raised against the stable unencapsulated mutant E. coli O7:K-, showed reduction but not lack of the capsular polysaccharide of encapsulated E. coli O7:K1, and better exposure of subcapsular epitopes, after incubation with 0.5x the MICs of antibiotics. Flow cytometric analysis of encapsulated E. coli exposed to netilmicin, ciprofloxacin, and fleroxacin revealed that the reduction in capsular material was homogeneous among the bacterial population. Treatment with cefepime and ceftriaxone induced two populations of bacteria that differed in the amount of K antigen present. These results indicate that sub-MICs of netilmicin, ceftriaxone, fleroxacin, and ciprofloxacin influenced complement-mediated opsonization, probably due to changes in the capsular polysaccharide structure.

Agglutination Tests↗

Antibiotic treatment of experimental pneumonic plague in mice.

A mouse model was developed to evaluate the efficacy of antibiotic treatment of pneumonic plague; streptomycin was compared to antibiotics with which there is little or no clinical experience. Infection was induced by inhalation of aerosolized Yersinia pestis organisms. Antibiotics were administered by intraperitoneal injection every 6 hours for 5 days, at doses that produced levels of drug in serum comparable to those observed in humans treated for other serious infections. These studies compared in vitro to in vivo activity and evaluated the efficacy of antibiotics started at different times after exposure. Early treatment (started 24 h after challenge, when 0 of 10 mice tested had positive blood cultures) with netilmicin, ciprofloxacin, ofloxacin, ceftriaxone, ceftazidime, aztreonam, ampicillin, and rifampin (but not cefazolin, cefotetan, or ceftizoxime) demonstrated efficacy comparable to streptomycin. Late treatment (started 42 h after exposure, when five of five mice tested had positive blood cultures) with netilmicin, ciprofloxacin, ofloxacin, and a high dose (20 mg/kg of body weight every 6 h) of gentamicin produced survival rates comparable to that with streptomycin, while all of the beta-lactam antibiotics (cefazolin, cefotetan, ceftriaxone, ceftazidime, aztreonam, and ampicillin) and rifampin were significantly inferior to streptomycin. In fact, all groups of mice treated late with beta-lactam antibiotics experienced accelerated mortality rates compared to normal-saline-treated control mice. These studies indicate that netilmicin, gentamicin, ciprofloxacin, and ofloxacin may be alternatives for the treatment of pneumonic plague in humans. However, the beta-lactam antibiotics are not recommended, based upon poor efficacy in this mouse model of pneumonic plague, particularly when pneumonic plague may be associated with bacteremia.

Animals↗

Analytical accuracy of determinations of aminoglycoside concentrations by enzyme multiplied immunoassay, fluorescence polarization immunoassay, and radioimmunoassay in the presence of heparin.

The accuracy of gentamicin, netilmicin, and tobramycin concentration determinations by enzyme multiplied immunoassay technique (EMIT; Syva Corp., Palo Alto, Calif.), fluorescence polarization immunoassay (TDx; Abbott Diagnostics, Irving, Tex.), and radioimmunoassay were compared in the presence of 0 to 3,000 USP units of porcine heparin per ml. Gentamicin, netilmicin, and tobramycin concentrations determined by EMIT decreased by 10 and 50% in the presence of 75 and 1,000 USP units/ml, 2 and 5 USP units/ml, and 2 and 7.5 USP units/ml, respectively. Accuracy of the TDx and radioimmunoassay determinations, however, were not affected by the presence of heparin. Blood samples for the determination of gentamicin, netilmicin, and tobramycin by EMIT should not be collected in evacuated heparinized tubes.

Aminoglycosides↗

Impact of a practical two-stage intervention on aminoglycoside usage.

To control aminoglycoside usage and costs, a two-stage intervention was implemented at this 1,000-bed, major Canadian teaching hospital. An informational stage, reviewing the therapeutic equivalence of netilmicin, gentamicin, and tobramycin in various internal publications, was followed by an automatic therapeutic interchange program. The intervention involved removing netilmicin from the formulary and substituting gentamicin for tobramycin. Comparing the 8-week pre-implementation period with the 24-week, post-implementation period, new orders for netilmicin declined from 42% to less than 1% of the total new aminoglycoside courses initiated. During the same time frame, new orders for gentamicin increased from 50% to 90%, orders for tobramycin remained stable at approximately 5.5%, and orders for amikacin remained unchanged at 1%. A retrospective health record review revealed a low incidence of microbiologically inappropriate interchanges. Pharmacy manpower requirements were minimal and prescriber acceptance was high. A +27,000 cost savings per year was estimated.

Aminoglycosides↗

[Initiation of systemic administration of antibiotics in treatment of invasive infection of burns].

OBJECTIVE: To optimize the systemic antibiotics in the treatment of the invasive infection of burns based on the successive monitoring of bacterial species harvested from the burn wound and subeschar tissues and their resistance to antibiotics. METHODS: The data of bacteriological monitoring of burn wound and subeschar tissues in our burn center from 1995 to 2000 were retrospectively analyzed, and the characteristics of distribution and resistance to antibiotics of 1 109 strains from the wound in 612 patients and subeschar tissues in 146 patients were compared statistically by dividing them into two periods, i.e. from 1995 to 1997 and 1998 to 2000, respectively. RESULTS: The percentage of Gram negative bacilli in identified strains was significantly higher than that of Gram positive cocci, and the majority of them were Pseudomonas and Enterobacteriaceae; Staphylococcus aureus comprised the majority of Gram positive cocci from 1998 to 2000, compared with the data collected in the period of from 1995 to 1997. The resistance of the Gram negative bacilli to Cephalosporins and Amikacin was increasing while the resistance of Pseudomonas to Netilmicin was decreasing from 18.52% of the tested strains down to 5.83%, and the resistance of Enterobacteriaceae to it was increasing from 18.75% to 55.79%. In addition, the resistance of Staphylococcus aureus to Netilmicin was down from 28.13% to 4.70%. Enterobacteriaceae were still sensitive to Imipenem, while the resistance of Pseudomonas to it became higher than that in the period from 1995 to 1997. CONCLUSION: The percentage of Gram negative bacilli in identified strains is significantly higher than that of Gram positive cocci and the pattern of their resistance to the antibiotics is changed meanwhile. Therefore, the choice of antibiotics for initial treatment of invasive infection in severe burns is a combination of Netilmicin and Imipenem, and, if Gram positive cocci is highly suspected, the first choice is Vancomycin.

Anti-Bacterial Agents↗

In vitro antimicrobial susceptibilities of 349 methicillin-resistant Staphylococcus aureus isolates from veterans.

Three hundred and forty-nine methicillin resistant Staphylococcus aureus (MRSA) isolates from veterans were tested (by disc agar diffusion) for their in vitro activity against 18 antimicrobial agents. At least 90% of the isolates were susceptible to bacitracin, nitrofurantoin, hydrogen peroxide, novobiocin, netilmicin and vancomycin. We feel that the aminoglycoside, netilmicin, might provide an alternative agent (to intravenously administered vancomycin) for treating multiply-antimicrobial resistant MRSA. In addition, hydrogen peroxide exhibited very good activity against the test isolates and may have some use as a topical agent for reduction of MRSA on skin and some mucous membranes. This study suggests that further evaluation of netilmicin and hydrogen peroxide (topical only) might be useful.

Anti-Bacterial Agents↗

Susceptibilities of coagulase-negative staphylococci to aminoglycosides antibiotics as compared by early bactericidy assays.

Twenty four strains of coagulase-negative staphylococci from clinically significant blood cultures were separated in four groups on the basis of oxacillin susceptibility and phenotype of resistance to aminoglycoside antibiotics. Susceptibility testing included disk diffusion testing, M.I.C. and M.B.C. determinations and finally, measurements, at sequential times (from 0 to 6 hours), of the bactericidal effect of aminoglycosides alone or combined with oxacillin or vancomycin. Aminoglycosides clinical use (gentamicin, netilmicin, tobramycin and amikacin) exhibited an efficient early bactericidy over the sensitive strains to any tested aminoglycosides and to oxacillin (group 1, 13 strains). When strains having a phenotype of resistance to kanamycin and neomycin (group 2, 4 strains) or kanamycin and tobramycin (group 3, 2 strains) were considered, amikacin inefficiency was assessed by time-killing assay even though disk diffusion testing as well as M.I.C. and M.B.C. determinations failed to demonstrate it. In the same way, only bactericidy measurements indicated the lack of activity of amikacin or netilmicin over strains exhibiting a phenotype of resistance to gentamicin plus kanamycin and tobramycin (group 4, 5 strains). Netilmicin appeared as the most active aminoglycoside over the strains studied. Crude results of disk diffusion testing might appear as an oversimplification, especially when coagulase-negative staphylococci are considered; the early-bactericidy assay findings were stressing for the need of interpreting the results of antibiotic testing on the ground of resistance mechanisms.

Aminoglycosides↗

[Effects of aminoglycosides on the rabbit in-vivo ERG].

We evaluated the retinal toxicity of aminoglycosides (gentamicin, sisomicin, netilmicin, tobramycin and amikacin) by ERG, before and after a single-shot intravitreal injection in rabbits. Gentamicin 200 micrograms abolished the c-wave one week after injection, only slightly diminishing the b-wave and the oscillatory potentials (OPs). Gentamicin 80 micrograms did not alter the ERG up to at least 8 weeks after injection. All the ERG components examined were abolished by 200 micrograms and were irreversibly suppressed by 80 micrograms of sisomicin for the entire period of follow-up. Netilmicin (200 micrograms) or tobramycin (200 micrograms) transiently suppressed the b-wave, c-wave and the OPs. Amikacin (200 micrograms) caused no ERG changes for at least 8 weeks after injection. The clinical doses for single-shot intravitreal injections that we recommend are 100 micrograms for gentamicin, 200 micrograms for netilmicin, 200 micrograms for tobramycin and 200-400 micrograms for amikacin.

Aminoglycosides↗

In vitro activity of dactimicin and other aminoglycosides against bacteria producing aminoglycoside-modifying enzymes.

Dactimicin is a new pseudo-disaccharide aminoglycoside, originally isolated from cultures of Dactylosporangium matsuzakienzae sp. nov., which is chemically related to astromicin. In this study the in vitro activity of dactimicin has been determined against strains of bacteria producing characterized aminoglycoside-modifying enzymes and has been compared with that of gentamicin, tobramycin, netilmicin and amikacin. Minimum inhibitory concentrations were determined using an agar incorporation technique in Mueller-Hinton agar with an inoculum of approximately 10(4) cfu. Dactimicin was resistant to inactivation by a number of different acetyltransferases (AAC), produced by species of the Enterobacteriaceae, most of which inactivated gentamicin, tobramycin and netilmicin. The exception was an AAC(3')-I produced by an isolate of Escherichia coli, which inactivated gentamicin and dactimicin but not tobramycin, netilmicin and amikacin. Dactimicin was inactivated by the adenyltransferases (AAD) AAD(2") and AAD(9), produced by Pseudomonas aeruginosa, but not by an AAD(4')(4"), produced by a strain of Staphylococcus aureus, nor by an AAD(2") produced by a strain of E. coli. Dactimicin was inactivated by a combination of a phosphotransferase (APH) APH(2") and an AAC(6') produced by strains of S. aureus. The results suggest that dactimicin may retain useful antibacterial activity against many gentamicin-resistant strains of bacteria belonging to the Enterobacteriaceae and some gentamicin-resistant strains of S. aureus.

Acetyltransferases↗

[Evolution of bacterial resistance to five aminoglycosides. A study of 3,354 strains isolated in a hospital milieu].

The authors studied the susceptibility to 5 aminoglycosides (amikacin, dibekacin, gentamicin, netilmicin and tobramycin) of 3,354 strains isolated at the Centre Hospitalier Sud in Bordeaux during 1987. The results are compared to those obtained in 1984 on 2,818 strains. Amikacin remains the most active aminoside against the Enterobacteriaceae and Acinetobacter; against Pseudomonas, tobramycin has become the best one at that time, as well as netilmicin against Staphylococcus aureus. Evolution: no significative increase of Enterobacteriaceae resistance to aminoglycosides was observed during the last 3 years except for Providencia and Serratia. For Acinetobacter and Pseudomonas, percentage of resistant strains is respectively two-fold and three-fold higher. Although resistance increased in that species, netilmicin and amikacin showed a still good activity against Staphylococcus aureus.

Acinetobacter↗