Netilmicin: Clinical Efficacy, Tolerance, and Toxicity

Netilmicin, a new semisynthetic aminoglycoside, was used in the treatment of 42 patients with serious gram-negative bacterial infections. Of the 40 evaluable patients, 24 (60%) were cured, and 8 (20%) had a favorable clinical response, for a total clinical response rate of 80%. Eight patients failed to respond; of these, three had undrained abscesses and two had severe granulocytopenia. Three of the patients who failed had organisms in which resistance to netilmicin developed during therapy, and in two of these three netilmicin was the only aminoglycoside to which resistance developed. Of the 37 patients evaluable for toxicity, 8 (22%) developed renal insufficiency. Two patients had mild but persistant elevation in serum creatinine. Three patients had nephrotoxicity while on gentamicin in the past. Pre-and posttherapy audiograms were done on 26 patients; none had hearing loss. Four patients had mild, transient asymptomatic elevations in alkaline phosphatase. The pretreatment clinical isolates were tested for in vitro susceptibility. The median minimal inhibitory concentration of netilmicin, gentamicin, and tobramycin ranged between 0.5 and 2 ug/ml. The median minimal inhibitory concentration of amikacin was approximately twofold higher. No clear in vitro superiority of one aminoglycoside over another was observed.Netilmicin, a newly developed semisynthetic analog of sisomicin, is active against a wide variety of aerobic gram-negative bacteria. Although its antimicrobial activity in vitro is similar to the other aminoglycosides (2, 4-6, 9, 10, 13, 17), it appears to be less nephrotoxic and ototoxic than these congeners in experimental animals (1,8,11). We undertook the present study to evaluate the efficacy and toxicity of netilmicin in infections in humans. This report is based on our experience with 42 patients. MATERIALS AND METHODSPatient studies. All patients were hospitalized at the Tufts-New England Medical Center. Patients selected for admission to the study had evidence of gram-negative bacterial infection which required an aminoglycoside for therapy, the only exclusions being children and pregnant women. Informed consent was obtained from each patient or next of kin before netilmicin treatment. Criteria for bacteremia included positive blood cultures with fever 238.3°C, hypotension, or chills. A separate category was suspected sepsis in which fever, hypotension, or chills were present but no growth of gram-negative bacteria was documented from blood cultures. Criteria for the diagnosis of pneumonia included roentgenological evidence of an infiltrate in addition to the presence of leukocytes and gram-negative organisms in secretions obtained by transtracheal aspiration or aspiration from an endotracheal tube. Criteria for urinary tract infection were cultures of 106 organisms per ml from voided urine specimens and fever (238.3°C) or dysuria, frequency, urgency, or pyuria. Criteria for peritonitis were fever, abdominal tenderness (usually with rebound), and polymorphonuclear leukocytes in ascitic fluid. ...

Section: Resultssupporting

confidence: 88%

Section: Antimicrob Agents Chemothersupporting

confidence: 52%

See 1 more Smart Citation

Netilmicin in Gram-Negative Bacterial Infections

Snydman

Tally

Landesman

et al. 1979

“…Table 1 shows the concentrations of gentamicin and netilmicin in the serum after 1, 3, or 14 10-mg/kg injections of either drug. The serum levels of both aminoglycosides were identical and similar to those found in humans (9,17). The half-lives of the two antibiotics in serum were not clinically different (Table 2).…”

Section: Methodssupporting

confidence: 73%

Influence of Single or Multiple Doses of Gentamicin and Netilmicin on Their Cortical, Medullary, and Papillary Distribution

Bergeron

Trottier

1979

In this study, the comparative intrarenal distribution and accumulation of both gentamicin and netilmicin were investigated in normal rats. The animals received 1, 3, or 14 injections of 10 mg of gentamicin or netilmicin per kg. A total of 324 animals and 648 kidneys were analyzed. These animals were sacrificed at from 1 h to 25 days after the intraperitoneal injections. At each timed interval, the serum, urine, cortex, medulla, and papilla were analyzed for antimicrobial content.The peak serum values of gentamicin (8 to 12 ,ug/ml) and netilnicin (9 to 14 ,ug/ ml) were close to those found in humans. There was a progressive increase in the cortical concentrations of both antibiotics from a low of 53 ,ug/g to a high of 719 ,ug/g when the animals were given increasing doses of the agents. At most timed intervals, the concentrations of gentamicin within the cortex were slightly lower than those of netilmicin. The accumulation of the drugs was also demonstrated in the medulla, where therapeutic levels could be detected for up to 25 days after the cessation of therapy. Even though gentamicin and netilmicin were transiently present in the papilla after 1 or 3 injections, both drugs could still be detected in the papilla on day 25 after 14 doses. The urinary concentration closely paralleled the papillary concentration. If applicable to humans, the persistence of high levels of both drugs within the medulla and papilla may have therapeutic implications.A better understanding of the intrarenal pharmacokinetics and distribution of antimicrobial agents might be of value in the proper choice of drugs for the treatment of pyelonephritis. Most people interested in the intrarenal distribution of aminoglycosides (6, 12, 13) have tried to correlate the cortical concentrations of these drugs with their toxicity (14). In pyelonephritis, bacterial growth is largely limited to the medulla and the papilla (20). The accumulation of aminoglycosides within these zones may be critical in the therapy of renal infections.Netilnicin has been reported to be less nephrotoxic than gentamicin (3,14). If this is true and if netilmicin can accumulate within all sections of the kidney without any apparent toxicity, the intrarenal kinetics of this antibiotic may provide information of therapeutic utility.The purpose of this study was to compare the cortical, medullary, and papillary distribution of gentamicin and netilmicin after one and multiple injections, which were designed to obtain a therapeutic serum range comparable to that in humans. MATERIALS AND METHODSWhite female Sprague-Dawley rats weighing between 200 and 280 g were used for all experiments.The animals were allowed free access to food and water. They were fed with standard rat diet free of antibiotics.Shortly before each experimental period, the rats were weighed, and the doses of antibiotics and anesthetics were determined accordingly. Each rat received 1 or 3 intraperitoneal doses of either gentamicin or netilmicin (10 mg/kg of body weight; the 3 doses were given 8 h apart) or 14 i...

“…We studied a large number of critically ill patients who received aminoglycoside antibiotics by appropriate dosing schedules, and we (10,12,20,21) in humans, although in rats, netilmicin is consistently less nephrotoxic (1,9,11). Third, our nephrotoxic patients showed abnormal tissue uptake early in treatment, before changes in serum creatinine occurred.…”

Section: Discussionmentioning

confidence: 99%

Clinical and pharmacokinetic characteristics of aminoglycoside nephrotoxicity in 201 critically ill patients

Schentag¹,

Cerra²,

Plaut³

1982

We studied 201 critically ill patients during 267 courses of gentamicin (139 courses) or tobramycin (128 courses) therapy. Clinical and pharmacokinetic data were obtained on 240 of 267 courses (120 courses each of gentamicin and tobramycin). Two judgments of nephrotoxicity and its cause were made independently in this study, using a clinical and a pharmacokinetic definition of nephrotoxicity. The two sets of criteria were generally in good agreement, as all but 10 of 41 patients who were judged nephrotoxic by pharmacokinetic criteria were independently judged nephrotoxic by the clinical definition. Groups of patients judged nontoxic did not differ from groups judged nephrotoxic in age, sex, weight, initial creatinine clearance, total dose given, duration of treatment, initial aminoglycoside trough serum levels, number of dosage adjustments, concurrent use of furosemide, or concurrent cephalosporins. Prior aminoglycosides (usually gentamicin) had been used more frequently in the nontoxic group (P < 0.05). Two major conclusions of this study are at variance with those of previous investigators: (i) we found no clinical parameters of value in predicting nephrotoxicity in critically ill patients; and (ii) aminoglycoside serum concentrations, once in the therapeutic range, were of limited value in prevention of aminoglycoside nephrotoxicity in our patients.We and others have previously shown that the various aminoglycosides differ in their intrinsic nephrotoxic potential in animals (1, 9, 11, 13) and humans (10,17,18,19). In such studies, both nontoxic and nephrotoxic patients must have precise control of the serum concentrations before the population can be analyzed for the factors predisposing to nephrotoxicity. We have treated 201 critically ill patients with suspected or proven infections, with aminoglycosides administered in regimens that were closely monitored by measured blood levels (17). Dosing adjustments were made as required to maintain the recommended concentration range. The judgment of nephrotoxicity was made independently by both clinical and pharmacokinetic criteria. Gentamicin was more frequently (24%) nephrotoxic than was tobramycin (12%). In this analysis, we compared all nontoxic patients with all nephrotoxic patients so as to use our large groups of nephrotoxic patients to define the characteristics of those who experienced renal damage when appropriately dosed with aminoglycosides. METHODSPatients. We gave 201 acutely ill patients 267 courses of aminoglycoside therapy. Pharmacokinetic and clinical data were available on 240 courses, which were used for analysis. The patients were older adults in critical care units, with serious infections complicating either major medical or surgical disorders. Most infections were intra-abdominal or pneumonic. Patients were entered into this study at the time of request for dosing and pharmacokinetic monitoring.Dosing and sample collection. Aminoglycosides were administered by intravenous infusion over 30 to 60 min. Dosing rates were determined initially by n...