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In vitro susceptibility studies with netilmicin: comparison of a 10-microgram netilmicin disk with a standardized 10-microgram gentamicin disk.

Netilmicin is a new, semisynthetic aminoglycoside antibiotic active against some gentamicin-resistant gram-negative bacteria. In this study we compared a 10-mug netilmicin disk with the standardized 10-mug gentamicin disk in terms of their abilities to predict probable clinical susceptibility to netilmicin. The agar dilution procedure of the International Collaborative Study of the World Health Organization and the U.S. Food and Drug Administration standardized disk test procedure were used. The gentamicin disk failed to predict the clinical susceptibility to netilmicin of 26 of 118 isolates previously shown by the agar dilution technique to to be netilmicin susceptible. The netilmicin disk correctly predicted probable susceptibility of all 26 isolates, including 20 shown by the agar dilution procedure to be resistant to gentamicin. These studies demonstrate the need for a separate netilmicin disk for use in agar diffusion disk susceptibility tests.

Bacteria

Importance of the aminoglycoside dosing regimen in the penicillin-netilmicin combination for treatment of Enterococcus faecalis-induced experimental endocarditis.

The penicillin-aminoglycoside combination is recommended for the treatment of systemic enterococcal infections. However, the optimal dosing regimen of the aminoglycoside remains to be elucidated. We evaluated the efficacy of penicillin, alone or in combination with various dosing regimens of netilmicin, for the treatment of experimental left-sided Enterococcus faecalis endocarditis in rabbits. Animals were injected intramuscularly for 4 days with penicillin alone or in combination with netilmicin in one of the following regimens: netilmicin at a low dose (2 mg/kg of body weight every 8 h), netilmicin at a high dose (4 mg/kg every 8 h), or netilmicin at a single daily high dose (12 mg/kg every 24 h). MICs and MBCs were 3.1 and 6.2 micrograms/ml and 8 and 8 micrograms/ml for penicillin and netilmicin, respectively. A netilmicin concentration of 4 micrograms/ml was the lowest concentration that achieved synergism with penicillin, as shown by the kill-curve method. Mean peak levels of netilmicin in serum were 5.6 (netilmicin at 2 mg/kg), 9.8 (netilmicin at 4 mg/kg), and 20.6 (netilmicin at 12 mg/kg) micrograms/ml. Mean penicillin levels in serum were constantly above the MIC. Penicillin plus netilmicin at a high dose given three times daily was more effective (P less than 0.05) than any other regimen in reducing bacterial titers in vegetations and was the only treatment that induced a significant bactericidal activity in rabbit serum during the trough. We concluded that divided doses of aminoglycoside are more effective than the same total dose given once daily in combination with penicillin. Our data suggest that prolonged levels of aminoglycoside in serum might be important to exhibit the greatest in vivo efficacy of the combination against E. faecalis. They also indicate that use of a reduced total daily dose of aminoglycoside or an increase in the interval between each dose might reduce the efficacy of therapy in animals with this type of infection.

Animals

Renal pharmacology of netilmicin.

Netilmicin (Sch 20569), a new semisynthetic aminoglycoside, was studied for its effects on kidney function and mechanisms by which it is handled by the kidneys. Measurements of glomerular filtration rate (GFR) and urinalysis in chronic rat studies indicated that the nephrotoxicity of netilmicin was remarkably less than that of gentamicin. Gentamicin caused a dose-related reduction in GFR in association with glucosuria and elevated fractional excretion of K(+). By contrast, high doses of netilmicin produced only slight reduction in GFR with increased fractional excretion of K(+) but without glucosuria. In separate experiments, rats were shown to excrete 71 to 90% of netilmicin or gentamicin in 24 h after daily intramuscular administration of doses of 20 or 40 mg/kg for 4 days. In acute experiments on anesthetized dogs, GFR and renal plasma flow were unaffected at serum levels of 11.0 +/- 0.6 mug/ml maintained by constant infusion of netilmicin for 5 h. The renal clearance of netilmicin was significantly correlated with GFR. The urinary output of netilmicin was 80.0 +/- 4.2% of the infusion rate and was independent of urine flow over the range of 0.04 to 0.33 ml/kg per min. Preferential accumulation of netilmicin occurred in the renal cortex; the cortex-serum and medulla-serum ratios were 9.9 +/- 1.2 and 4.2 +/- 0.6, respectively. In addition, the extraction ratio of netilmicin, which was lower than that of inulin, suggested that netilmicin reabsorption occurs in the proximal tubule and results in cortical accumulation. It is concluded that netilmicin, like gentamicin, is excreted by the dog kidney by glomerular filtration plus limited reabsorption. However, the new drug is characterized by low intrinsic nephrotoxicity in rats.

Animals

In vitro study of netilmicin compared with other aminoglycosides.

Netilmicin (Sch 20569) is an ethyl derivative of gentamicin C(1a) that is active against most Enterobacteriaceae, Pseudomonas aeruginosa, and Staphylococcus aureus isolates. Among 342 clinical isolates tested, all staphylococci; 92% of Escherichia coli, 93% of Klebsiella pneumoniae, and 92% of Enterobacter were inhibited by 0.8 mug or less of netilmicin per ml, but only 78% of P. aeruginosa were inhibited by 3.1 mug or less per ml. Most clinical isolates of enterococci, Serratia marcescens, and Providencia were not inhibited by 3.1 mug of netilmicin per ml. Like other aminoglycosides, the netilmicin in vitro activity was markedly influenced by the growth medium used, with activity decreased by sodium, calcium, and magnesium. Netilmicin was more active at alkaline pH. Addition of magnesium to Pseudomonas or Serratia pretreated with netilmicin produced inhibition of killing. Netilmicin was more active than gentamicin, sisomicin, tobramycin, or amikacin against E. coli and K. pneumoniae. Netilmicin inhibited growth of all gentamicin-resistant isolates of Klebsiella and Citrobacter tested, but only 73% of E. coli; Pseudomonas and Providencia were resistant to netilmicin. Most Serratia (95%) and indole-positive Proteus (83%) isolates were resistant to netilmicin but were inhibited by amikacin.

Amikacin

Effect and pharmacokinetics of netilmicin given as bolus intramuscular administration: an open comparative trial versus amikacin and fosfomycin in elderly patients affected by urinary tract infections.

A randomized comparative open clinical trial was performed on 96 hospitalized patients of both sexes, most of whom (84.4%) over 60 years of age, affected by simple and complicated urinary tract infections. Patients were divided in three unequal sized groups and treated with a single administration of netilmicin (5 mg/kg intramuscularly), of amikacin (15 mg/kg i.m.) or of fosfomycin (3 g per os). Patients were evaluated clinically and microbiologically before the beginning of the therapy, 1, 7, 15, 30 days thereafter and at monthly intervals, up to the 18th month, after the drug administration. The pharmacokinetic study was performed in six elderly patients of both sexes, apparently in good general health, except for their urinary tract infections. Symptoms of urinary tract infection disappeared in 50 out of 53 (94.3%) patients treated with netilmicin 14.48 +/- 9.6 hours after the drug administration, in 22 out of 23 (95.6%) of those treated with amikacin after 31.9 +/- 14.3 hours and in 16 (84.2%) out of 19 of symptomatic patients treated with fosfomycin after 37.5 +/- 10.6 hours. The disappearance of symptoms in netilmicin-treated patients is significantly (p less than 0.01) faster than in the other two groups. Twenty-four hours after the administration, netilmicin and amikacin produced sterilization of the cultures in more than 95% of cases, fosfomycin in 90%. Of those patients in which sterilization of cultures was achieved about 70%, in the netilmicin group, and 50% in the other two treatment groups had sterile urine cultures after one month. At the end of the study, 18 months later, more than 60% of the patients treated with netilmicin, the infection had not recurred in comparison with 39.1% and 50% in the amikacin and fosfomycin groups respectively. If only the patients with uncomplicated infections were considered, 88.9% and 83.3% had sterile cultures after 1 and 18 months respectively in the netilmicin group. The corresponding figures in other two groups were: 66.7% for both time intervals in the case of amikacin and 60% both for 1 and 18 months in the case of fosfomycin. The pharmacokinetic results indicate that netilmicin is rapidly absorbed and distributed from the injection site, possesses a beta half-life of about two hours and is mainly excreted by the kidneys. The single dose administration produces very high urinary concentrations of the drug in the first 24 hours and concentrations above 4 micrograms/ml, the 90% minimum inhibitory concentration cut-off point for netilmicin sensitive strains, for four days(ABSTRACT TRUNCATED AT 400 WORDS)

Age Factors

Effect of E. coli pyelonephritis on the intracortical accumulation kinetics of gentamicin and netilmicin in rats.

The role of serum levels on the intrarenal accumulation kinetics of gentamicin and netilmicin in normal and infected kidneys was evaluated in a short-term infusion model in conscious rats. Female Sprague-Dawley rats were infused over a period of 6 h with gentamicin and netilmicin achieving individual steady-state serum levels ranging from 0.5 to 120 micrograms/ml. The model of pyelonephritis used resulted in severe left pyelonephritis and mild right pyelonephritis. Only the right infected kidneys were studied. Gentamicin and netilmicin cortical concentrations were analysed as a function of serum levels by linear (least-squares regression analysis) and non-linear regression. For the non-linear regression analysis, the Michaelis-Menten kinetic was the best fitting curve. Steady-state elevation of serum concentrations of gentamicin and netilmicin was associated with a non-linear increase of cortical concentrations in normal kidneys, suggesting a saturable process. By contrast, in the mildly-infected right kidneys, the steady-state elevation of serum concentrations of gentamicin was associated with a linear increase of cortical concentrations while the accumulation kinetic of netilmicin showed a saturable process. At lower serum levels (therapeutic range, from 0.5 to 15 micrograms/ml) both gentamicin and netilmicin showed a first order kinetics of accumulation and netilmicin accumulated less than gentamicin in normal kidneys (p = 0.0004). By contrast, the uptake of netilmicin was higher in the right infected kidneys, as compared to the uptake of netilmicin in the normal kidneys, (p = 0.00005), and as compared to gentamicin in the respective kidneys. We conclude that renal infection modifies the intrarenal accumulation of aminoglycosides.

Animals

Kinetics of netilmicin and gentamicin.

The kinetic parameters of netilmicin were studied in normal human subjects. In the intravenous study a steady-state was obtained in 4 subjects by the constant infusion of 2 mg/kg of netilmicin during the first hour followed by 0.5 mg/kg/hr for each of three successive hours. Creatinine clearance was greater than the simultaneous serum and renal clearance of netilmicin. In the intramuscular study 6 subjects received a single injection of 1 mg/kg of netilmicin followed by the same dose of gentamicin 1 wk later. A mean peak serum levels of 3.9 microgram/ml was found for both antibiotics, but the mean serum half-life of netilmicin was shorter than that of gentamicin. Doubling the intramuscular dose of netilmicin approximately doubled the peak serum level. In both studies 75% to 90% of the netilmicin was recovered in the urine within the first 24 hr. Netilmicin appears to be primarily excreted by glomerular filtration. The apparent volume of distribution was similar to that reported for other related aminoglycosides. Netilmicin and gentamicin have similar kinetic parameters. There were wide individual differences among normal subjects with both drugs.

Female

Distribution kinetics of netilmicin in human blister fluid: effect of renal impairment.

The pharmacokinetics of netilmicin in plasma and blister fluid were compared in 10 healthy volunteers with normal renal function and 10 voluntary patients with varying degrees of renal impairment. Netilmicin kinetics in plasma were characterized by an open two-compartment kinetic model. For the study of the kinetics of the antibiotic in blister fluid a specific kinetic distribution model was employed. In the healthy volunteers the plasma kinetics of netilmicin showed a behaviour similar to that of other aminoglycoside antibiotics, although a high blister/plasma partition coefficient was obtained, with a mean value of 4.27 +/- 1.65. The transfer of netilmicin in blister fluid governed by the constants K1b/Vb and Kbl had mean values of 0.19 +/- 0.09 h-1 l-1 and 0.25 +/- 0.10 h-1, respectively. In the patients with renal impairment plasma and blister fluid antibiotic levels showed a progressive accumulation. In these patients the affinity of netilmicin for blister fluid was significantly altered. The blister/plasma partition coefficient in this group of patients had a mean value of 2.65 +/- 1.33; the decrease being statistically significant (p = 0.023) with respect to the value obtained in the healthy volunteers. Similarly, the exit constant of netilmicin from blister fluid (Kb1) showed a statistically significant increase (p = 0.035) in the patients with renal impairment. The findings point to a loss of affinity of netilmicin for blister fluid as a result of renal impairment. Linear and logarithmic relationships were established between some pharmacokinetic parameters and creatinine clearance. Dosage schedules are proposed for netilmicin in patients with renal impairment.

Adult

Cefazolin and netilmicin serum levels during and after cardiac surgery with cardiopulmonary bypass.

The kinetics of cefazolin and netilmicin were studied in 10 patients undergoing elective cardiac surgery with hemodilution and cardiopulmonary bypass (CPB). During surgery, but before CPB, cefazolin, 25 mg/kg, and netilmicin, 2 mg/kg, were administered intravenously over 30 minutes. For the 48-hour period following CPB, cefazolin, 25 mg/kg, and netilmicin, 1 mg/kg, were administered intravenously every 8 hours. Initiation of CPB was accompanied by a 28% to 30% decrease in hematocrit and serum antibiotic levels. At the conclusion of surgery, cefazolin and netilmicin serum levels were 41 +/- 12 micrograms/L and 2.5 +/- 0.6 micrograms/mL (mean +/- SD), respectively. During the postoperative period, cefazolin levels were consistently greater than the minimum inhibitory concentration (MIC) for sensitive bacteria (4 micrograms/mL); average netilmicin levels were greater than MIC of sensitive bacteria (2 micrograms/mL) for 2 hours after antibiotic infusion. The netilmicin trough levels were 0.6 +/- 0.5 micrograms/mL. Pharmacokinetic parameters were determined using a model-independent method, and gave the following results during surgery: cefazolin--elimination half-life, 231 minutes, total body clearance, 1.05 mL/kg/min, and steady-state volume of distribution, 243 mL/kg. The values for netilmicin were 249 minutes, 1.18 mL/kg/min, and 353 mL/kg, respectively. Postoperatively there were no significant changes in the disposition of cefazolin, but the elimination half-life of netilmicin was shorter (124 minutes, P less than 0.01) and the total body clearance greater (3.58 mL/kg/min, P less than 0.01) than during surgery.

Adolescent

Pharmacokinetic properties of netilmicin in newborn infants.

Netilmicin and gentamicin susceptibilities of 258 gram-negative organisms and 25 strains of Staphylococcus aureus were nearly identical. The pharmacokinetic properties of netilmicin were evaluated in 101 newborn infants and related to birth weight, gestational age, chronological age, and route of administration. Mean peak serum concentrations of 5.6 to 6.9 and 7.8 to 8.4 mug/ml were observed 30 min after 3- and 4-mg/kg doses, respectively, were given intramuscularly. The peak concentrations were directly related to gestational age. The average serum half-life values varied from 3.4 to 4.7 h and in general were inversely related to birth weight, gestational age, and postnatal age. The pharmacokinetics of netilmicin in 10 infants were similar after intramuscular and intravenous administration. A comparative study of netilmicin and gentamicin in seven neonates revealed greater variability in serum concentrations of gentamicin and a shorter half-life for netilmicin. There was evidence of accumulation of netilmicin in 12 low-birth weight, premature infants who received 4-mg/kg doses for an average of 6.4 days. Serum and urine levels of netilmicin were measured up to 11 days after discontinuation of the drug. These data are well characterized by a two-compartment model. Additional studies of efficacy and long-term toxicity of netilmicin in neonates are necessary.

Bacteria

Netilmicin: a review of toxicity in laboratory animals.

The data on the toxicity of netilmicin in laboratory animals as well as preliminary data in man are reviewed. Netilmicin is less toxic to the VIIIth nerve than is gentamicin in all species tested. The data suggest that it probably is less ototoxic than tobramycin, although confirmatory studies should be performed. Netilmicin is also nephrotoxic than gentamicin in all species tested. It is less nephrotoxic than tobramycin in the rat and dog. Comparisons in the rat suggest that netilmicin has a flat dose--response curve that resembles the curve produced by streptomycin. In animals, netilmicin produces more neuromuscular blockade than gentamicin; however, neuromuscular blockade with aminoglycosides in man is rare and thus far no episodes have been associated with netilmicin during clinical investigation. Initial clinical studies in man indicate that netilmicin is efficacious and well tolerated. Presently available data suggest that netilmicin offers distinct advantages over older aminoglycosides. Final conclusions must await prospective randomized double-blind trials in man.

Abnormalities, Drug-Induced

In vitro activity of netilmicin, gentamicin, and amikacin.

The in vitro activity of netilmicin (Sch 20569), a new semisynthetic derivative of gentamicin, was compared with that of gentamicin and amikacin. One hundred and ninety-two clinical isolates of Enterobacteriaceae, Pseudomonas aeruginosa, and Staphylococcus aureus were tested using both agar and broth dilution techniques. Netilmicin was comparable to gentamicin, with the following exceptions: (i) for Serratia marcescens and P. aeruginosa, gentamicin was more active than netilmicin; (ii) all strains of Escherichia coli, Klebsiella, Enterobacter, Proteus mirabilis, and Citrobacter freundii, which were resistant to gentamicin, were susceptible to netilmicin; (iii) some strains of S. marcescens, indole-positive Proteus, and Providencia, which were resistant to gentamicin, were susceptible to netilmicin. Netilmicin was more active than amikacin for all Enterobacteriaceae and S. aureus and equal to amikacin in activity against gentamicin-susceptible strains of P. aeruginosa. All strains of P. aeruginosa, resistant to gentamicin, were also resistant to netilmicin but were susceptible to amikacin. Minimal inhibitory concentrations (MICs) obtained with broth and agar showed no significant differences except for P. mirabilis, where broth MICs were twofold greater than agar MICs, and for P. aeruginosa, where agar MICs were twofold higher than broth MICs. The minimal bactericidal concentration (MBC) was either identical to or within one twofold dilution of the MIC for the strains tested. A 100-fold increase in inoculum size produced less increase in MIC and MBC with netilmicin than with gentamicin or amikacin.

Amikacin

Ionic binding, adaptive resistance and post-antibiotic effect of netilmicin and ciprofloxacin.

Ionic binding, post-antibiotic effect (PAE) and adaptive resistance to netilmicin and ciprofloxacin were investigated in 11 distinct clinical isolates. Both netilmicin and ciprofloxacin showed concentration dependent kill and PAE when bacteria were exposed to these antibiotics at 37 degrees C. The effects of netilmicin were maintained at 4 degrees C, when there is no energy dependent cell uptake of antibiotic, but were partially inhibited by exposure to NaCl and EDTA although not by Ca++. This supports the concept that ionic binding to the bacterial cell wall is important in the initial uptake of netilmicin. Ciprofloxacin showed no such effects at 4 degrees C. Adaptive resistance (reduced bacterial kill on second exposure) occurred with both netilmicin and ciprofloxacin but was seen more frequently with netilmicin. It persisted longer than classical PAE but, even after continuous exposure, was not enough to suggest a loss of kill with a twice daily dosing regimen of netilmicin or ciprofloxacin.

Ciprofloxacin

Pharmacokinetic and toxicological evaluation of a once-daily regimen versus conventional schedules of netilmicin and amikacin.

The safety and pharmacokinetics of netilmicin (6.6 mg/kg) and amikacin (14.5 mg/kg) once daily (od) have been compared to their corresponding conventional schedules thrice daily (tid), and twice daily (bd), in patients (20 per group) suffering from pelvic inflammatory disease. Sensitive criteria of early renal and auditory alterations, namely urinary excretion of phospholipids and audiometry over a wide frequency range (0.25-18 kHz), respectively, were used. The first criterion (phospholipiduria) was validated by an animal study which demonstrated that rats receiving poly-L-aspartic acid, which protects against gentamicin-induced nephrotoxicity, are also protected against renal phospholipidosis and phospholipiduria caused by this antibiotic. On that basis, netilmicin od was better tolerated than netilmicin tid. Amikacin caused less phospholipiduria than netilmicin, and, given od, resulted in little increase over baseline (95% CI, 95-147% increase). Reduction in threshold by greater than or equal to 15 dB for frequencies between 10-18 kHz occurred in nine of 19 patients receiving netilmicin tid compared with three or four of 19 or 20 patients treated with netilmicin od or amikacin (od or bd). However, changes at lower frequencies (0.25-8 kHz) were infrequent with all regimens (from 0/19 to 2/20). In conclusion, these very sensitive tests of nephro- and oto-toxicity suggest that od dosing of amikacin or netilmicin is, if anything, safer than bd or tid dosing.

Adult

Effect of concomitant administration of piperacillin on the dispositions of netilmicin and tobramycin in patients with end-stage renal disease.

The effect of piperacillin administration on the dispositions of netilmicin and tobramycin was assessed in 12 chronic hemodialysis patients. Six subjects each received netilmicin (2 mg/kg) or tobramycin (2 mg/kg) alone and in combination with piperacillin (4 g every 12 h for four doses). Subjects also received a single dose of piperacillin (4 g) on a separate occasion. The serum concentration-versus-time profiles of netilmicin and tobramycin were biexponential. The terminal elimination half-life (t1/2 beta) of tobramycin was markedly reduced (59.62 +/- 25.18 [mean +/- standard deviation] versus 24.71 +/- 5.41 h) and total body clearance (CLP) was significantly increased in the presence of piperacillin (3.45 +/- 1.61 versus 7.16 +/- 1.64 ml/min). In contrast, the t1/2 beta (41.80 +/- 13.24 versus 40.07 +/- 10.37 h) and CLP (5.11 +/- 2.15 versus 5.55 +/- 2.32 ml/min) of netilmicin were not significantly altered when netilmicin was administered in combination with piperacillin. No change in the central or steady-state volume of distribution of netilmicin or tobramycin was observed. The disposition of piperacillin in hemodialysis patients was not altered in the presence of either aminoglycoside antibiotic. Although no adjustment in netilmicin dosing is required, tobramycin should be administered more frequently when given concomitantly with piperacillin to hemodialysis patients to avoid prolonged periods of subtherapeutic concentrations.

Adult

Netilmicin: clinical evaluation of efficacy and toxicity of a new aminoglycoside.

The efficacy and toxicity of netilmicin, a new semisynthetic aminoglycoside, was clinically evaluated in fifty-two patients with moderate to severe infections with Gram-negative rods or Staph. aureus. Average duration of treatment was 14 days and mean total dose 2,960 mg. One-hour mean value of netilmicin serum concentration was 6.4 microgram/ml and mean trough value 1.2 microgram/ml. Forty-four patients were cured or improved. In twenty-one of them the effect could be attributed to netilmicin alone; the other twenty-three had a combined therapy. No improvement took place in five, but four of them could not be regarded as netilmicin failure. One patient with Pseudomonas aeruginosa infection was possible failure. The sensitivity of the causative bacteria to netilmicin was studied and compared with amikacin, gentamicin, sisomicin and tobramycin. Vestibular function and hearing acuity was thoroughly examined by electronystagmography and audiography. Drug-related VIIIth nerve damage could not be confirmed in any of our patients. Five patients showed a rise of serum creatinine of 30 mumol/l. This shows that netilmicin, similar to other aminoglycosides, is a potential nephrotoxic drug. Netilmicin appears to be an efficacious aminoglycoside and the oto- and nephrotoxicity is low, if careful attention is paid to the renal function and the serum concentrations of the drug.

Adolescent

Therapeutic experience with netilmicin.

Netilmicin, a new aminoglycoside antibiotic, was used to treat 19 patients with urinary tract infection and 5 with systemic infection. The causal organisms were Escherichia coli (in 2), Klebsiella pneumoniae (in 4), Serratia marcescens (in 12) and Pseudomonas aeruginosa (in 7); 1 patient was infected with two of these organisms. All the isolates of causal organisms except one of Serratia were initially sensitive to netilmicin but many were resistant to other aminoglycosides. Sixteen of the urinary tract infections responded to netilmicin therapy, although relapse occurred in three patients. Two of the three patients with musculoskeletal infection responded to combined therapy with surgery and netilmicin; the other patient responded to the same regimen but with carbenicillin added. Netilmicin cured pneumonia in one patient but failed in the other patient with pneumonia, who had leukemia. Superinfection occurred in five patients with urinary tract infection. Adverse reactions to netilmicin were minor. Netilmicin may prove to be a useful agent, particularly for infections due to multiresistant Klebsiella or Serratia, or when prolonged aminoglycoside therapy is required.

Adolescent

In vitro synergistic effect of netilmicin, a new aminoglycoside antibiotic.

The combination of netilmicin (Sch 20569) with carbenicillin, cefazolin, chloramphenicol, and clindamycin was evaluated by in vitro tests against 91 clinical isolates of Pseudomonas, Klebsiella, and Escherichia coli. Combinations were considered to show synergy if there was a fourfold or greater reduction in minimal inhibitory concentration values of both antibiotics when combined. Synergy of netilmicin with carbenicillin could be demonstrated against 21 of 46 Pseudomonas isolates. Comparison of the synergy of carbenicillin with netilmicin or gentamicin showed that netilmicin was less active than gentamicin against Pseudomonas aeruginosa. However, at therapeutic concentrations of the antibiotics, significant differences were not observed. Synergy of netilmicin and cefazolin was demonstrated against only 1 of 21 Klebsiella strains tested, but partial synergy was found for 12 of 20 isolates. Synergy and antagonism were uncommon with the netilmicin-chloramphenicol and netilmicin-clindamycin combinations against E. coli and Pseudomonas.

Anti-Bacterial Agents