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[Importance of the study of the minimal bactericidal time of serum in the choice of optimal treatment of neonatal septicemias].

Rapid eradication of bacteria in bloodstream is critical for the outcome in neonatal bacterial sepsis. Two groups of neonates with E. coli K1 sepsis without purulent meningitis were studied. Group I (n = 14) received cefotaxime IV (100 mg.kg-1 D-1) plus netilmicin (4 mg.kg-1 D-1); group II (n = 8) received amoxicillin/clavulanic acid IV (100/10 mg.kg-1 D-1) plus netilmicin (4 mg.kg-1 D-1). Both groups were identical. For all strains MICs of cefotaxime, amoxicillin/clavulanic acid, netilmicin were less than 0.2, 4 and 1 mg/l respectively. Serum bactericidal activity (SBA) was determined for each patient (peak sample). The SBA was defined as the greatest dilution in which 99,99% of the inoculum was killed. Time-kill curves were performed with 1:16 dilutions of peak serum samples to measure the kinetic of bacterial killing. The minimal bactericidal time of serum (MBTS) was defined as the minimal time required to observe a decrease of more than 4 log CFU/ml of the bacterial inoculum. Samples (10 microliters) were taken at 1 h intervals over a 6 h period and at 24 h for quantitative culture. All patients cured. Median SBA were respectively 1/128 and 1/64 for group I and II. However, mean MBTS for groups I and II were respectively 1.2 h +/- 0.8 and 3.9 h +/- 1.4. Killing was more rapid in group I (p less than 0.01). The MBTS may be a clinically useful adjunctive test when optimal therapy would be expected.

Amoxicillin↗

Early indicators of nephrotoxicity: comparison of two antibiotics.

The aim of the study was the evaluation of the clinical efficacy and the kidney tolerance of ceftazidime in comparison with netilmicin in pediatric patients. Forty subjects, ranging from six months to ten years of age were randomly allocated in two groups and treated either with ceftazidime (80-100 mg/kg/day) or netilmicin (6 mg/kg/day). A control group of twenty subjects was selected in order to establish the normal values of beta 2-microglobulin and urinary enzymes excretion. beta 2-microglobulin, enzymuria, cylindruria and urinary osmolability were estimated, as well as hematological parameters. Ceftazidime was as efficacious as netilmicin in the clinical outcome and in addition it did not cause any pathological change in early markers of tubular damage.

Ceftazidime↗

[Diffusion of amikacin in the lungs].

The authors report their findings on amikacin concentrations in serum and in the lungs, its diffusion in the parenchyma of the lungs--evaluated from the ratio tissue/serum concentrations, and they also compare their results with those registered during a study on dibekacin, tobramycin and netilmicin, designed according to the same protocol. Ten patients with bronchial carcinoma who had to undergo chirurgical excision, received 5 IM injections at 12-hourly intervals. The dose administrated at each injection was 7.5 mg/kg. The assay of amikacin was realized by HPLC. Serum concentrations at the presumed peak (17 micrograms/ml) and 12 hours after that were somewhat lower than those reported by other authors. The mean tissue concentrations 2 h 20 min. after the last injection were 14,95 +/- 4,52 micrograms/g in the normal parenchyma, and 16,18 +/- 3,67 micrograms/g in the pathological parenchyma. The ratio concentrations in the tissues and in serum were comparable for both the normal and pathological parenchyma. Compared to dibekacin, tobramycin and netilmicin, this study confirms the large distribution of the aminoglycosides in the lung parenchyma. The behaviour of dibekacin and tobramycin with regard to the pathological parenchyma is rather comparable; netilmicin better penetrates into the normal parenchyma, and the diffusion of amikacin is parallel for both the normal and pathological tissues.

Amikacin↗

[An early and specific indicator of aminoglycoside nephrotoxicity: isoenzyme B of urinary N-acetyl-beta-D-glucosaminidase (NAG)].

88 patients (aged 55-96 years) with severe infections were treated during ten days with one of four different aminoglycosides: gentamicin, dibekacin, netilmicin (3 mg/kg/day) or amikacin (15 mg/kg/day). Creatinine clearance and urinary N-acetyl-glucosaminidase (NAG) activity were measured daily. In addition, NAG isoenzyme patterns were determined on the day of maximal urinary NAG excretion. Aminoglycoside-induced acute renal failure was more prevalent in the gentamicin group (42.8%) than in the dibekacin, netilmicin or amikacin groups (42.8%, 5.5% and 0% respectively). No relationship was found between total urinary NAG activity and nephrotoxic risk. Conversely, significantly elevated levels (p less than 0.001) of B isoenzyme were detected in the gentamicin group, whereas the highest A and I isoenzyme levels were found in the dibekacin and netilmicin groups. These results suggest that functional enzymuria with preferential urinary excretion of A and I isoenzymes should be distinguished from lesional enzymuria with preferential urinary excretion of the B isoenzyme. According to our data, the NAG-B isoenzyme may possibly be a specific marker of aminoglycoside nephrotoxicity.

Acetylglucosaminidase↗

Emergence of tobramycin-resistant S. epidermidis possessing aminoglycoside modifying enzymes and bacteremic superinfection during empiric therapy of febrile neutropenic episodes.

During a randomized clinical trial comparing tobramycin plus ticarcillin to netilmicin plus ticarcillin as empiric therapy of febrile neutropenic patients, Staphylococcus epidermidis emerged as the predominate superinfecting pathogen in tobramycin recipients. Overall clinical response was 68% (44/65 responding) in tobramycin/ticarcillin recipients and 73% (45/62) in netilmicin/ticarcillin recipients. However, 5/65 tobramycin/ticarcillin treated episodes were complicated by bacteremic superinfection with Staphylococcus epidermidis, as compared to 0/62 netilmicin/ticarcillin treated episodes (p less than 0.05). Four of the five bacteremic strains produced aminoglycoside adenylating enzyme ANT 4', 4''. Prior colonization of patients with identical strains was demonstrated by plasmid profile analysis, antibiograms and biotyping with the API Staph-Ident system. During the trial, 36 consecutive patients were studied for colonization patterns with coagulase-negative staphylococci. S. epidermidis accounted for 566/831 (68%) isolates of coagulase-negative staphylococci recovered from surveillance cultures. Tobramycin-resistant strains were acquired in 2/17, 4/12 and 9/14 patients during trimethoprim/sulfamethoxazole, netilmicin/ticarcillin and tobramycin/ticarcillin therapy, respectively. Prior to aminoglycoside therapy, 77% of strains were susceptible to less than or equal to 8 micrograms/ml of tobramycin, but only 35% and 28% were susceptible to tobramycin after initiation of tobramycin/ticarcillin and netilmicin/ticarcillin therapy, respectively. In contrast, greater than or equal to 93% of isolates were susceptible to netilmicin before and after aminoglycoside therapy. Absence of several sites susceptible to modification by aminoglycoside inactivating enzymes produced by staphylococci may give netilmicin a therapeutic advantage in the therapy of febrile neutropenic patients.

Adult↗

[In vitro study of the synergistic effect of cefotiam- aminoglycoside combinations on strains of low susceptibility to this cephalosporin].

Antibacterial activity of cefotiam associated with gentamicin, tobramycin, netilmicin, or amikacin against Enterobacteriaceae strains either moderately susceptible (MIC = 4 to 32 micrograms/ml, 14 strains) or resistant (MIC = 64 to 512 micrograms/ml, 22 strains) to cefotiam was studied using the checkerboard method. High rates of synergic associations (FIC index less than or equal to 0.5) were found, with variations according to the aminoglycoside: 65% for tobramycin and netilmicin, 76% for amikacin, and 81% for gentamicin. Activity of cefotiam is increased by the synergic effect of these associations: of the 36 strains tested, 83, 78 and 76% became susceptible to cefotiam (MIC less than or equal to 4 micrograms/ml) associated with tobramycin, netilmicin or gentamicin, and amikacin respectively.

Amikacin↗

Peroperative systemic prophylaxis in colorectal surgery.

In an effort to reduce infection rates in elective colorectal surgery to acceptable levels without oral non-absorbable antimicrobials, using only a short course of systemic antimicrobials, 50 patients were studied in a multicentre trial. Each patient received metronidazole for anti-anaerobic coverage. The anti-aerobic coverage consisted of netilmicin, cefuroxime or placebo, administered in a double-blind manner. Five out of 36 evaluable patients had an infection at the operation site. Two patients had peritonitis (one metronidazole-netilmicin and one metronidazole-placebo) and three had a wound abscess in the abdominal wall (all metronidazole-placebo). It is concluded that a short course of peroperative systemic prophylaxis with metronidazole and netilmicin or cefuroxime--without the use of oral non-absorbable antimicrobials--gave acceptable results in the centres studied.

Cefuroxime↗

Compatibility of furosemide with aminoglycoside admixtures.

The compatibility of furosemide with i.v. admixtures containing each of five different aminoglycosides was studied. Admixtures of amikacin 2 mg/ml, gentamicin 1.6 mg/ml, kanamycin 2 mg/ml, netilmicin 1.5 mg/ml, and tobramycin 1.6 mg/ml (as the sulfate salts) were prepared in both 5% dextrose injection and 0.9% sodium chloride injection in minibags. Furosemide injection 4 ml (40 mg) was then added to each admixture, and the admixtures were examined visually and microscopically for precipitate. The macroscopic and microscopic evaluations were repeated 15 minutes and 24 hours after mixing. To simulate Y-site injection of furosemide, furosemide injection 1 ml (10 mg) was added to 1 ml of each aminoglycoside admixture in a syringe. For admixtures in which precipitates formed, the pH was recorded before and after adding furosemide to subsequent admixtures and also after dropwise addition of 1N sodium hydroxide until the precipitate dissolved. Precipitates were identified using spectrophotometric analysis and melting point determinations. Addition of furosemide resulted in a precipitate only in admixtures containing gentamicin sulfate or netilmicin sulfate; the results for the simulated Y-site injection study were the same. Spectrophotometric analysis and melting point determinations revealed that the precipitate was furosemide. Because furosemide precipitates when added to admixtures containing either gentamicin sulfate or netilmicin sulfate in 5% dextrose injection or 0.9% sodium chloride injection, furosemide should be administered separately or the i.v. tubing should be flushed thoroughly before and after administering this drug via a Y-injection site.

Amikacin↗

Outer membrane proteins and lipopolysaccharide changes after exposure of Pseudomonas aeruginosa to antibacterial drugs.

Many studies show the low sensitivity of P. aeruginosa to antimicrobial agents, due to the permeability degree of the outer membrane (OM). Since the alterations of porins and lipopolysaccharides (LPS) are responsible for permeability to antibacterial drugs, the aim of this study was to evaluate the sub-M.I.C. effects of different antibiotics on the OM components. The M.I.C.s of five P. aeruginosa strains were determined and sub-M.I.C.s. versus PD-131,628, a new difluoroquinolone, aztreonam and netilmicin were calculated. The OM components were extracted before and after contact with the antibacterial drugs. We noted a decrease in M.I.C. values in two strains, and simultaneously an increase in the 19 and 38 Kd bands after using aztreonam. The M.I.C.s tended to increase in three strains after using netilmicin. The electrophoresis profile showed a decrease in the 38, 41 and 45 Kd bands and in one strain also in the 19 Kd band. The use of the quinolone did not significantly modify the M.I.C. values, although an evident increase in 38 and 41 Kd bands occurred in three strains. LPS alterations were observed with aztreonam and netilmicin, but not when PD 131,628 was used.

Anti-Bacterial Agents↗

Antibiotic prophylaxis in cardiac surgery.

BACKGROUND: A prospective, randomised study was conducted among 1009 cardiac surgery patients in order to compare the prophylactic efficacy of a second generation cephalosporin (cefuroxime) given as single shot, versus a broad spectrum double regimen (amoxycillin-netilmicin). METHODS: Cefuroxime received 501 patients (Group A), while a 4-day combination of amoxycillin-netilimicin 508 patients (Group B). RESULTS: There were found no statistically significant differences either in infection rate or the kind of infection between the two groups. Single shot cefuroxime prophylaxis was just as effective, as a 4-day combination of amoxycillin and netilmicin. Total infection rate was 5.6% (n=28) in Group A and 5.7% (n=29) in Group B. Respiratory tract infection was the most frequently registered in both groups; 2.6% in Group A and 2.9% in Group B. Sternal wound and catheter-related infection rates were 0.6% and 1% in both groups, respectively. There were no side effects due to the given antibiotics. CONCLUSIONS: A single shot of cefuroxime prophylaxis is equally effective and safe as a 4-day regimen with amoxycillin and netilmicin.

Aged↗

Aminoglycoside dosage in hemodialysis patients.

Regulating aminoglycoside dosage in patients undergoing hemodialysis is difficult because its elimination depends entirely on renal function and because the therapeutic margin is narrow. Guidelines for aminoglycoside dosage were derived from published population-based kinetics and investigated in a prospective clinical study over a 12-month period in 50 consecutive patients undergoing hemodialysis with acute (70%) or chronic (30%) renal failure. Based on body weight, each patient received one loading dose (1.5 mg/kg) and a daily maintenance dose (0.5 mg/kg) of netilmicin. The dosage interval was 24 hours. On each hemodialysis day, the dose of netilmicin was given immediately after hemodialysis. Each posthemodialysis dose (1.3 mg/kg) was the sum of the daily maintenance dose plus a supplementary dose to replace the amount of the drug removed during hemodialysis. A blood sample was taken at the start and the end of each hemodialysis and one hour after the start of the posthemodialysis dosage. Netilmicin plasma concentrations were determined by substrate-labeled fluorescence immunoassay. The mean (+/- standard deviation) peak plasma concentration of the pooled data for all patients was 7.5 +/- 2.7 mg/L, and the mean trough level was 3.6 +/- 1.3 mg/L. The theoretically postulated range of therapeutic peak levels (5-10 mg/L) was the same as in patients with normal renal function, whereas the theoretically postulated range of therapeutic trough levels (2.2-5.0 mg/L) was considerably higher than in healthy persons. Peak and trough levels within the postulated range were achieved in 81% of the patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

Characterization of mutants of the 6'-N-acetyltransferase encoded by the multiresistance transposon Tn1331: effect of Phen171-to-Leu171 and Tyr80-to-Cys80 substitutions.

The Klebsiella pneumoniae plasmid pJHCMW1 harbors a copy of Tn1331, a multiresistance transposon that includes the aac(6')-Ib gene which encodes a 6'-N-aminoglycoside acetyltransferase. This gene was mutagenized using the mutator Escherichia coli XL1-Red. Two plasmids with a single nucleotide mutation in aac(6')-Ib were selected for further analysis: pDP1 and pDP6. Plasmid pDP1 codes for a mutant enzyme, AAC(6')-IbDP1, that has the Phe171 replaced by a Leu residue. This mutant derivative showed a lower specific activity than the wild-type enzyme when either kanamycin (Km) or its semisynthetic derivative amikacin (Ak) were used as substrates in enzymatic assays performed at 30 degrees C. Furthermore, AAC(6')-IbDP1 showed a change of specificity of substrate when incubated at 42 degrees C. While its acetylating activity for Km was higher at this temperature than at 30 degrees C, it had its ability to utilize Ak as substrate for acetylation considerably reduced. Accordingly, minimal inhibitory concentration assays showed that E. coli(pDP1) was resistant to Ak at 37 degrees C but susceptible at 42 degrees C. The same assays showed that E. coli(pDP1) was highly resistant to Km at either 37 degrees C or 42 degrees C. A high level of resistance to Ak was observed for E. coli(pJHCMW1) which harbors the wild-type AAC(6')-Ib at either 37 or 42 degrees C. Extension of the analyses to other aminoglycosides showed that the enzymatic activity of AAC(6')-IbDP1 as well as the E. coli(pDP1) MICs for netilmicin dropped at 42 degrees C as was the case for Ak. These results could indicate that at 42 degrees C the mutant adopts a conformation that makes it unable to efficiently acetylate aminoglycoside molecules substituted in the C-1amino group of the deoxystreptamine moiety. Plasmid pDP6 encodes the mutant AAC(6')-IbDP6 which has the Tyr80 substituted by a Cys residue. E. coli(pDP6) exhibited reduced MICs for Ak, Km, tobramycin, and netilmicin. Analysis of the acetylating activity of AAC(6')-IbDP6 showed only marginal levels of activity when either Ak, Km, tobramycin, or netilmicin were used as substrates.

Acetylation↗

Sensitivity of gram-negative bacteria to six aminoglycoside antibiotics.

An in vitro study of the susceptibility of 201 newly isolated strains of gramnegative bacteria to six aminoglycoside antibiotics (kanamycin, amikacin, gentamicin, tobramycin, sisomicin and netilmicin) was performed by the twofold dilution method in fluid medium. Both the minimal inhibitory concentration and the minimal bacteridical concentration were determined. Overall, tobramycin seemed the most effective of the drugs studied. Netilmicin, the new derivative from sisomicin, compared favourably with the other drugs tested, but may, on theoretical grounds, offer the additional advantage of retained efficacy in the face of developing bacterial resistance. Not unexpectedly, amikacin appeared to be the most promising of the drugs studied in its action against Pseudomonas aeruginosa. Amikacin and netilmicin appeared to be the most effective of this group of antibiotics against Klebsiella species.

Amikacin↗

The penetration of antibiotics into human pancreas.

In order to analyse the penetration of two antibiotics (mezlocillin and metronidazole) which cover the spectrum of microorganisms involved in pancreatic infection, we determined their concentration in pancreatic tissue, juice and cyst fluid in 16 patients undergoing pancreatic surgery. In addition, the external pancreatic fistula fluid of one patient was analysed for antibiotic concentration and bacterial counts during a seven-day treatment with mezlocillin, metronidazole and netilmicin (i.v.). Antibiotic concentrations were determined by HPLC between 16 and 210 (median 74) min after i.v. administration of 4 g mezlocillin and 500 mg metronidazole, respectively. The median concentration of mezlocillin was 23.2 (range: 3.1-37.4) mg/kg, 15.9 (range: 4.2-55.0) mg/l and 9.9 (range: 5.2-14.8) mg/l in pancreatic tissue, juice and cyst fluid, respectively. The median concentration of metronidazole was 5.1 (range: 1.8-13.0) mg/kg, 8.5 (range: 3.6-16.2) mg/l and 1.2 (0.9-1.4) mg/l in pancreatic tissue, juice and cyst fluid, respectively. From the fistula patient, seven different bacteria were cultured (five aerobic and two anaerobic isolates); their concentration in fistula fluid ranged from 10(5) to 10(7) CFU/ml. The bacteria sensitive for mezlocillin and metronidazole disappeared after four days of i.v. treatment, whereas the two isolates sensitive for netilmicin showed continuous growth seven days after i.v. treatment. The peak concentrations for mezlocillin, metronidazole and netilmicin in the fistula fluid were 6.8 mg/l, 5.6 mg/l and less than 0.1 mg/l, respectively.

Adenocarcinoma↗

Characterization of aminoglycoside-lipid interactions and development of a refined model for ototoxicity testing.

Aminoglycoside interactions with various phospholipids were measured in three model systems and compared with the ototoxicities of the drugs: (a) competition for [14C]neomycin binding; (b) competition for 45Ca2+ binding; and (c) effect on surface pressure of monomolecular lipid films. The efficacies of the antibiotics in displacing neomycin from phosphatidylserine, phosphatidylinositol or phosphatidylinositol bisphosphate were netilmicin greater than neomycin greater than or equal to gentamicin; the efficacies in displacing calcium from phosphatidylinositol, phosphatidylinositol phosphate or phosphatidylinositol bisphosphate were netilmicin greater than gentamicin greater than neomycin much greater than kanamycin greater than spectinomycin. Neither measure correlated well with the ototoxicities of the drugs which were quantitated at equimolar drug concentrations in cochlear perfusions: neomycin greater than gentamicin greater than or equal to tobramycin greater than netilmicin greater than or equal to amikacin. When monomolecular films of phosphatidylcholine with phosphatidylserine, cardiolipin, phosphatidylinositol, or phosphatidylinositol phosphate or bisphosphate were challenged with neomycin, the phosphatidylinositol bisphosphate film showed a unique dose-dependent increase in surface pressure while the others showed a decrease or no significant effect. The abilities of aminoglycosides to increase the surface pressure of a film of phosphatidylcholine:phosphatidylinositol bisphosphate (1:1 molar ratio) in the presence of 3 mM CaCl2 correlated well with their toxicities. Non-ototoxic cations increased the film pressure or left it unaffected. The results confirm the unique interactions between aminoglycosides and phosphatidylinositol bisphosphate as a possible basis of a mechanism of toxicity and development of a drug-screening system.

Aminoglycosides↗

Streptomycin and its analogues are potent inhibitors of the hypotonicity-induced Ca2+ entry and Cl- channel activity.

Streptomycin is a common antibiotic used in culture media. It is also a known blocker of stretch-activated and mechanosensitive ion channels in neurons and cardiac myocytes. But very little information is available on its effect in the regulation of epithelial ion channels. Osmotic swelling is a kind of mechanical stretch. The opening of stretch-activated Ca(2+) channels contributes to hypotonicity-induced Ca(2+) influx which is necessary for the activation of volume-regulated Cl(-) channels in human cervical cancer cells. This study aimed to investigate the role of streptomycin in cell volume regulation. Treatment of cervical cancer SiHa cells with streptomycin and its analogues (gentamicin and netilmicin) did not affect the basal cytosolic Ca(2+) ([Ca(2+)](i)) level. But it attenuated the hypotonicity-stimulated increase of [Ca(2+)](i) in a dose-dependent manner with half-maximal inhibitory concentrations (IC(50)) of 25, 90 and 200 microM for streptomycin, gentamicin and netilmicin, respectively, when measured at room temperature. In contrast, under free extracellular Ca(2+) condition, hypotonic stress only induced a small, progressive increase of [Ca(2+)](i), while 500 microM streptomycin did not affect this Ca(2+) signaling. Streptomycin and its analogues (gentamicin and netilmicin) also inhibited the activation of volume-regulated Cl(-) channels in a dose-dependent manner with IC(50) of 30, 95 and 250 microM at room temperature, respectively. Chronic culture with 50 microM streptomycin downregulates the activity of volume-regulated Cl(-) channels and retards the process of regulatory volume decrease in SiHa cells and MDCK cells. We suggest that using cells chronically cultured with streptomycin to study epithelial ion channels risks studying cellular and molecular pathology rather than physiology.

Animals↗

Randomized trials of aminoglycoside antibiotics: quantitative overview.

Individual randomized trials comparing aminoglycosides have usually involved a sample size inadequate for reliable detection of small to moderate differences. In a search for overall effects that might not be apparent from any single trial, a quantitative overview of all randomized studies comparing amikacin, gentamicin, netilmicin, sisomicin, and tobramycin was performed. These aminoglycosides appeared equally efficacious, except that tobramycin seemed less effective than sisomicin. Patients given gentamicin or sisomicin seemed to run a higher risk of nephrotoxicity than those given amikacin; the risk for patients receiving tobramycin was lower than that for patients given gentamicin but higher than that for those given netilmicin. The only statistically significant difference with regard to auditory toxicity was a lower risk among patients receiving netilmicin than among those given amikacin or tobramycin. Meaningful differences in toxicity may exist for individual aminoglycosides given in efficacious doses. Future trials must include sample sizes sufficient to detect differences of the magnitudes observed in this overview. In the absence of such data, the overview may guide clinicians in determining the risk-to-benefit ratio for a particular aminoglycoside, especially for patients at high risk of toxicity.

Aminoglycosides↗

Antibiotic susceptibility of streptococcal strains associated with infective endocarditis.

Seventy-six strains of various species of streptococci isolated from patients with infective endocarditis were tested for their susceptibility to 13 antibiotics by an agar dilution method. The antibiotics tested were: benzyl-penicillin, ampicillin, cefotaxime, vancomycin, erythromycin, rifampicin, pristinamycin, gentamicin, netilmicin, tobramycin, amikacin, dibekacin and streptomycin. Excluding enterococci, 91% of strains were sensitive to benzylpenicillin. Resistance to benzylpenicillin was only found in some strains of S. sanguis I, S. sanguis II and S. mitis. Enterococci were more sensitive to ampicillin. Cefotaxime was highly active against all strains, except enterococci. Vancomycin was active against all strains. Resistance to erythromycin was found in 16% of isolates. Rifampicin and pristinamycin were highly active against all strains, except some enterococci. Gentamicin and netilmicin were the most active of the six aminoglycosides tested. High level resistance to streptomycin was seen in six strains. Overall, S. agalactiae was more resistant to the aminoglycosides than the other species. Among the non-groupable streptococci, strains of S. mitis, S. sanguis I and S. sanguis II were the least sensitive to many antibiotics. Benzylpenicillin remains the antibiotic of choice for the treatment of IE caused by streptococci. If the MIC exceeds 0.1 mg l-1, an aminoglycoside (netilmicin or gentamicin) should be added and the duration of treatment increased from 4 to 6 weeks.

Aminoglycosides↗