Comparison of Netilmicin with Gentamicin in the Therapy of Experimental Escherichia coli Meningitis

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: 65%

Pharmacokinetic Properties of Netilmicin in Newborn Infants

Siegel

McCracken

Thomas

et al. 1979

“…Penetration of aminoglycosides into bronchial secretions and cerebrospinal fluid is limited to approximately 20% of the concentrations in serum, and therefore it may be difficult to achieve therapeutic concentrations of drug in these areas without inducing nephrotoxicity (15,24). Since most antibiotics enter respiratory fluids by passive diffusion (19), these drugs may be cleared from the bronchial lumen by passive reabsorption when concentrations in blood fall below bronchial concentrations as well as by the mucociliary apparatus.…”

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confidence: 99%

Gentamicin dosing strategies for dogs with subclinical renal dysfunction

Frazier

Riviere

1987

Twenty-six subtotally nephrectomized dogs were used as a model for subclinical renal dysfunction to evaluate the nephrotoxic potential of gentamicin administered according to four different dosage regimens. Dosages were individualized based on the pharmacokinetic disposition of drug in each dog. Gentamicin at 3.75 + 0.15 mg/kg (mean ± standard error of the mean, total daily dose) was given for 12 days in two or three divided daily doses (BID and TID, respectively) or in a 2-h or 4-h once-daily variable-rate infusion (2HI and 4HI, respectively) with loading dose. Analyses of serum chemistries and pharmacokinetic data were performed on the ratio of pretreatment versus posttreatment parameters in individual animals. While serum chemistries and histopathology revealed no significant differences in toxicity between treatment groups, pharmacokinetic analysis revealed a significant difference in the ratio of pretreatment versus posttreatment gentamicin clearance (1.35 ± 0.22, BID; 2.44 ± 0.52, TID; 0.91 ± 0.08, 2HI; 0.91 ± 0.07, 4HI). By using mean population pharmacokinetic parameters (all dogs), predicted times for each treatment group administered 3.75 mg/kg per day to achieve concentrations in serum above the MICs of 2, 4, 6, and 8 ,ug/ml, respectively, were 7.8, 4.2, 2.0, and 0.6 (BID); 6.1, 3.0, 0.5, and 0.2 (TID); 7.1, 5.3, 4.2, and 3.5 (2HI); and 7.4, 5.8, 4.8, and 4.0 (4HI) h daily. This study suggests that decreasing the total daily dosage of drug may decrease the incidence of gentamicininduced nephrotoxicity. Regardless of the dosage regimen, however, regimens may differ significantly in predicted therapeutic efficacy. Predicted 30-min postdosing concentrations in serum were lowest in dogs administered drug TID, and gentamicin clearance decreased in this group with treatment, suggesting that this regimen may be the least efficacious as well as the most prone to causing future nephrotoxicity.The incidence of nephrotoxicity secondary to therapy with gentamicin and other aminoglycosides has been well documented. However, this class of drugs remains an essential therapeutic agent for the treatment of severe gram-negative infections. Traditionally, clinicians have altered doses based on serum creatinine or creatinine clearance in an effort to minimize toxicity. Individuals with compensated subclinical renal dysfunction marked by a decreased number of functional nephrons and normal serum creatinine levels present a diagnostic dilemma, requiring that dosage alteration be based on individual clearance of drug. Decreasing the dosage based on clearance does not preclude toxicity, however, since exposure to drug on a per-nephron basis is increased in patients with reduced functional renal mass (4,8).Previous studies have suggested that some dosage regimens may be less nephrotoxic than others. High peak and high trough concentrations in serum have been implicated as risk factors for development of nephrotoxicity in humans (27). Studies in experimental animals have shown that increasing the dosage interval may be less ne...

“…The test organisms were grown overnight in tryptic soy broth, centrifuged at 3,000 rpm for 15 min, suspended in saline, and diluted to ensure a final inoculum of 105 CFU. Meningitis was produced in 2-to 3-kg New Zealand white rabbits as described previously (21,24 Arterial blood samples (3 ml) and simultaneous CSF samples (0.2 ml) were collected at 0, 2, 4, 6, and 8 h of therapy. The CSF samples were cultured quantitatively with serial 10-fold dilutions in 0.9% NaCl and tryptic soy agar pour plates.…”

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confidence: 99%

Mecillinam-Ampicillin Synergism in Experimental Enterobacteriaceae Meningitis

Scheld

Fink

Fletcher

et al. 1979

The in vitro activities of mecillinam, a new f)-amidinopenicilhin, and ampicillin, alone and in combination, against an Escherichia coli strain and a Klebsiella pneumoniae strain were compared, and these results were correlated with their respective activities in vivo in experimental meningitis. The mecillinam-ampicillin combination was synergistic in vitro against both strains when tested by a modified checkerboard technique (bacteriostatic synergy). However when quantitative bactericidal synergy studies were made, the relative bactericidal rate of the combination was more rapid than that of either drug alone ("bactericidal synergy") against the Escherichia coli isolate only. In a rabbit model of Enterobacteriaceae meningitis, in vivo bactericidal activity correlated with results obtained in vitro. Both drugs were administered by continuous intravenous infusion for 8 h. Serum and cerebrospinal fluid antibiotic levels were similar to those achieved in humans. Cerebrospinal fluid bacterial concentrations (colonyforming units [CFU] per milliliter) were quantitatively titrated at 2-h intervals. Both drugs, alone or the combination, were ineffective against the K. pneumoniae strain in vivo (change in titer <1 log in 8 h). In contrast, the combination produced a markedly enhanced bactericidal effect against the E. coli strain (mean + standard deviation, decrease of log1o CFU per milliliter of 3.65 ± 1.02) compared with those of ampicillin alone (decrease of log1o CFU per milliter of 0.07 ± 0.8) and mecillinam alone (decrease of logio CFU per milliliter of 1.6 ± 0.05) (P < 0.001). When bactericidal synergism can be demonstrated for mecillinam-ampicillin in vitro in a case of gram-negative-bacillary meningitis this combination may be useful in the therapy of the illness.