Bactericidal Efficacy of Sch 20569 and Amikacin Against Gentamicin-Sensitive and -Resistant Organisms

Netilmicin and gentamicin susceptibilities of 258 gram-negative organisms and 25 strains of Staphylococcus aureus were nearly identical. The pharmacokinetic properties of netilrnicin 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 ,ug/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.Netilmicin is a new semisynthetic aminoglycoside that is a 1-N-ethyl sisomicin derivative produced by Micromonospora inyoensis. Its antimicrobial spectrum is similar to that of gentamicin with an added advantage that an increasing number of Enterobacteriaceae possess adenylating enzymes mediating resistance to gentamicin, but not to netilmicin (4,10,16,21,28). Animal studies indicate that substantially less ototoxicity and nephrotoxicity result from repeated doses of netilmicin than of gentamicin (9,12,16). In an experimental rabbit model ofEscherichia coli meningitis, netilmicin has also been shown to have greater bactericidal activity in cerebrospinal fluid' than does gentamicin (24). These observations suggest that netilmicin may be potentially useful for therapy of neonatal bacterial infections.In this study we have evaluated the pharmacokinetics of netilnicin in 101 neonates and related these properties to birth weight, gestational age, chronological age, and route of administration. We have also measured netilmicin in serum and/or urine for as long as 12 days after discontinuation of therapy and have fit these data to a two-compartment model as has been described for aminoglycosides in older children and adults (3,17,20,25,30). MATERIALS AND METHODSSusceptibility studies. The susceptibilities to gentamicin and netilmicin of 258 gram-negative organisms and 25 Staphylococcus aureus strains isolated from blood, cerebrospinal fluid, or urine of sick neonates and from rectal culture of normal newborns were determined by a modified agar plate dilution method (1) with a multiple inoculating apparatus (27). Serial twofold dilutions of laboratory standards of net...

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confidence: 88%

Pharmacokinetic Properties of Netilmicin in Newborn Infants

Siegel

McCracken

Thomas

et al. 1979

“…Netilmicin (Sch 20569), an agent differing from sisomicin by the presence of an ethyl group at the 1-N position of the deoxystreptamine moiety, has recently been provided for in vitro work. Initial animal toxicity studies indicated that this agent may be less oto-and nephrotoxic than gentamicin (5). Our study compares the in vitro activity of netilmicin with those of gentamicin, tobramycin, and amikacin against recent isolates of P. aeruginosa and various Enterobacteriaceae.…”

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confidence: 99%

Comparative Activity of Netilmicin, Gentamicin, Amikacin, and Tobramycin Against Pseudomonas aeruginosa and Enterobacteriaceae

Briedis

Robson

1976

Netilmicin (Sch 20569), a semisynthetic aminoglycoside antibiotic, was compared with gentamicin, tobramycin, and amikacin against 242 clinical isolates of Pseudomonas and Enterobacteriaceae . The minimum inhibitory concentration (MIC) was determined in both solid and liquid media. Netilmicin exhibited typical aminoglycoside properties, such as little effect of inoculum size on MIC, relatively small gap between MIC and minimum bactericidal concentration, and potentiation of anti- Pseudomonas activity in the presence of carbenicillin. Netilmicin provided no advantage in antimicrobial activity over gentamicin for either Pseudomonas or Enterobacteriaceae . Nearly complete cross-resistance to netilmicin was encountered with isolates resistant to gentamicin in either solid or liquid media. Netilmicin was less active than gentamicin against isolates of Pseudomonas and Providencia . Major discrepancies between MIC values determined in agar as opposed to those determined in broth were encountered for most isolates of Pseudomonas but also, depending upon antibiotic tested, for between 15 and 40% of isolates of Enterobacteriaceae . This new aminoglycoside agent will be useful clinically only if it is shown to be significantly less toxic than presently available analogues.

“…Chemically, it is 1-N-ethyl sisomicin, an analog of gentamicin Cla. Theoretical advantages of netilmicin are threefold: (i) an increased in vitro bactericidal activity over gentamicin against many strains of Enterobacteriaceae (1-3, 5, 6, 10, 11, 13, 15-17, 20, 22, 23); (ii) the inhibition of gentamicin-resistant strains when the resistance is associated with one of the gentamicininactivating acetylases (aminoglycoside acetylase-3i, -ii, or -iii) or an adenylase (aminoglycoside nucleotidylase-2"), which have been common modes of resistance among Enterobacter species, Escherichia coli, and Pseudomonas aeruginosa (4,16,18); (iii) relative freedom from ototoxicity and reduced nephrotoxicity in experimental animals (12,20). Also, there is a suggestion that the serum levels may be more predictable than those of gentamicin (19).…”

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confidence: 99%

Netilmicin: Clinical Efficacy, Tolerance, and Toxicity

Panwalker

Malow

Zimelis

et al. 1978

Netilmicin, a new aminoglycoside antibiotic, has increased in vitro bactericidal activity against many strains of Enterobacteriaceae as compared to other aminoglycosides. It is a poor substrate for some of the common gentamicin-inactivating enzymes, and it has minimal toxicity in experimental animals. In 27 hospitalized patients, clinical cure was achieved in all, and the initial infecting organism persisted in only one. Therapeutic serum and urine levels were easily obtained in most patients. No ototoxicity was observed in two patients whose treatment required inordinately high serum levels and in whom other risk factors were present. Ototoxicity in 1 of 21 patients studied was unilateral, partially reversible, and not associated with high serum levels. Although nephrotoxicity occurred in 4 of 25 patients (16%), other host factors could have accounted for the toxicity in two patients. A new observation, not noted with other aminoglycoside antibiotics, was the elevation of serum alkaline phosphatase in 43% of the patients studied.