Netilmicin Clinical Efficacy, Tolerance, And Toxicity

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Feb. 1978, p. 170-1760066-4804/78/1302-0170$02.00/0Copyright i 1978 American Society for Microbiology

Vol. 13, No. 2

Printed in U.S.A.

Netilmicin: Clinical Efficacy, Tolerance, and ToxicityANAND P. PANWALKER,* JAMES B. MALOW, VICTORIA M. ZIMELIS, AND

GEORGE G. JACKSON

University of Illinois Hospital and the Section of Infectious Diseases, Department ofMedicine, AbrahamLincoln School ofMedicine, University of Illinois College ofMedicine, Chicago, Illinois 60680

Received for publication 29 August 1977

Netilmicin, a new aminoglycoside antibiotic, has increased in vitro bactericidalactivity against many strains of Enterobacteriaceae as compared to other ami-noglycosides. It is a poor substrate for some of the common gentamicin-inactivat-ing enzymes, and it has minimal toxicity in experimental animals. In 27 hospital-ized patients, clinical cure was achieved in all, and the initial infecting organismpersisted in only one. Therapeutic serum and urine levels were easily obtainedin most patients. No ototoxicity was observed in two patients whose treatmentrequired inordinately high serum levels and in whom other risk factors werepresent. Ototoxicity in 1 of 21 patients studied was unilateral, partially reversible,and not associated with high serum levels. Although nephrotoxicity occurred in4 of 25 patients (16%), other host factors could have accounted for the toxicityin two patients. A new observation, not noted with other aminoglycoside anti-biotics, was the elevation of serum alkaline phosphatase in 43% of the patientsstudied.

Serious infections caused by aerobic gram-negative bacilli continue to be a major cause ofmorbidity and mortality of hospital patients.Their treatment is one of the principal indica-tions for the use of aminoglycoside antibiotics.A new aminoglycoside antibiotic, netilmicin, isa member of the gentamicin family of drugs.Chemically, it is 1-N-ethyl sisomicin, an analogof gentamicin Cla. Theoretical advantages ofnetilmicin are threefold: (i) an increased in vitrobactericidal activity over gentamicin againstmany strains of Enterobacteriaceae (1-3, 5, 6,10, 11, 13, 15-17, 20, 22, 23); (ii) the inhibitionof gentamicin-resistant strains when the resis-tance is associated with one of the gentamicin-inactivating acetylases (aminoglycoside acety-lase-3i, -ii, or -iii) or an adenylase (aminoglyco-side nucleotidylase-2"), which have been com-mon modes of resistance among Enterobacterspecies, Escherichia coli, and Pseudomonasaeruginosa (4, 16, 18); (iii) relative freedom fromototoxicity and reduced nephrotoxicity in exper-imental animals (12, 20). Also, there is a sugges-tion that the serum levels may be more predict-able than those of gentamicin (19). These favor-able features of netilmicin suggest the possibilityof more effective therapy of serious gram-nega-tive bacterial infections with diminished drugtoxicity and formed the basis for the investiga-tions reported here.

MATERIAIS AND METHODSThirty-one patients on the Medical and Surgical

Services of the University of Illinois Hospital enteredthe study. Four patients who received netilmicin forless than 48 h were excluded, two had nonbacterial"chemical" peritonitis, one died of sepsis after a singleinjection of netilmicin, and one withdrew from thestudy. The age distribution of the remaining 27 pa-tients was 16 to 85 years (mean, 43). There were 18females and 9 males. The underlying diseases were:hemoproliferative malignancy, 2; cirrhosis and hepa-titis, 7; paraplegia, 3; renal transplantation, 3; chronicrenal failure, 1; uretero-ileal conduit after resection ofbladder carcinoma, 3; diabetes mellitus, 1; and sicklethalassemia, 1. The condition of the patients wascritical in five, serious in six, and fair to good in theremainder. Other appropriate antibiotics were usedconcomitantly in four patients. Fever, chills, hypoten-sion, or all three were associated with bacteremia.Urinary tract infections were diagnosed on the basisof characteristic signs, symptoms, and bacteriuria(>100,000/mi) in midstream or catheter specimens.Three patients with the classical clinical syndrome ofacute pyelonephritis and pyuria were included, al-though no significant bacteriuria was demonstrated.Localization procedures such as intravenous pyelo-grams and fluorescent staining for antibody-coatedbacteria were performed in most patients with urinarytract infections. Patients with pneumonia had fever,sputum production, new pulmonary infiltrates onchest roentgenograms, and persistent isolation of thesame organism from sputum. Clinical features, re-peated isolation of the same gram-negative organisms

170

NETILMICIN: CLINICAL EFFICACY 171

from wounds and surgical specimens, and classicalradiological signs were the criteria for the diagnosisof soft-tissue infections and osteomyelitis.

Dosage. After informed consent was obtained, ini-tial treatment was started at 4.5, 6.0, or 7.5 mg/kgper day in divided doses at 8-h intervals; the higherdosage schedules were used in severely ill patients.Alterations in treatment were based on serum anti-biotic levels and serum creatinines. Eight patients whohad thrombocytopenia, shock, or severe illness re-ceived intravenous therapy; the remainder receivedintramuscular injections.Monitoring toxicity. Routine laboratory studies

performed before, during, and after therapy includeda complete hemogram, urine analysis, serum glutamicoxalacetic transaminase (SGOT), alkaline phospha-tase, serum creatinine, blood sugar, and serum electro-lytes. Where possible, creatinine clearances were mea-sured. In patients with urinary tract infection, quan-titative pyuria was measured (normal, <25,000 leuko-cytes/ml). Audiograms were done before or within 24h of treatment in 21 patients and again after treatment.When possible, tests were done in a soundproof roomwith an Audiotone Royal audiometer (Division Indus-tries, Phoenix, Ariz., model AUI-SP 3066). In lieu ofcaloric testing, patients were questioned and observedregarding the development of tinnitus, dizziness, orataxia.

Ototoxicity was defined as a mean decrease ofgreater than 10 decibels in auditory acuity in the rangeof 250 to 8,000 Hz and/or a decrease of at least 15decibels in two or more frequencies in either ear.Nephrotoxicity was defined as an increase in serumcreatinine of 0.4 mg/dl or greater, if the initial serumcreatinine was less than 2.0 mg/dl, or an increase of0.8 mg/dl or greater, if the initial creatinine wasgreater than 2.0 mg/dl. Nephrotoxicity was "definite"if no other causes of renal insufficiency (e.g., hypoten-sion, dehydration, papillary necrosis, etc.) were foundin the 72-h period before measured rise in serumcreatinine. If another possible etiology existed to ac-count for the rise in serum creatinine, it was termed"possible" nephrotoxicity.

Microbiological studies. Cultures of blood, urine,and other appropriate sites were obtained before, dur-ing, and after treatment and, in the case of urinaryinfections, at 2 and 4 weeks after completion of ther-apy. Species of bacteria were identified by routinemethods in the clinical bacteriology laboratory. Aserial tube dilution method with tryptose phosphatebroth was used to determine the minimal inhibitoryconcentration (MIC) of netilmicin and gentamicin formost study strains, but for comparative purposes somestrains were also studied using Mueller-Hinton broth.Serum and urine levels. Peak and trough serum

levels of netilmicin were measured frequently duringtreatment with the agar well diffusion method, usingStaphylococcus epidermidis (ATCC 27626) as the in-dicator strain. On days 3 to 6 of treatment, an 8-hurine collection with periodic serum levels was ob-tained to study the excretion of netilmicin. Simulta-neously, a creatinine clearance was measured.

Patient evaluation. Patients with bacteremiaand/or severe tissue infections were considered bac-

teriologically and clinically cured if all signs and symp-toms disappeared and the infecting organism was erad-icated. For urinary tract infections, symptomatic im-provement and elimination of infecting organisms forat least 4 weeks post-treatment was considered a cure.If there was superinfection, reinfection, or relapse, thecure was appropriately qualified.

RESULTSThirty-one patients received netilmicin. Of

these, four received less than 48 h of treatmentand were excluded from analysis. The suscepti-bility of the organisms recovered in the studyand 130 other clinical isolates at the UniversityHospital are shown in Fig. 1. The MICs for thestudy strains measured in tryptose phosphatebroth ranged from 1 to 32 ,ug/ml. The range ofMICs for the other clinical isolates was 0.25 to125 ,ug/ml, although the MIC did not exceed 8.0,ug/ml in most. For 26 strains tested in Mueller-Hinton broth, the MIC was two- to eightfoldlower. A majority of peak serum levels exceededthe MIC of the organisms (in tryptose phosphatebroth), and the urinary concentrations of thedrug were always above the MIC. In patientswith a serum creatinine value <2.0 mg/dl whoreceived intramuscular injections, there was astepwise increment in peak (1 h postdose) andtrough (8 h postdose) serum levels for threerising dosage schedules of 4.5, 6.0, and 7.5 mg/kgper day (Fig. 2). A majority of the peak levelsin each dosage category were in the "desirable"(4 to 8,ug/ml) range (Fig. 3). Urine excretion ofnetilmicin measured during the 8-h interval be-tween doses was a direct function of creatinineclearance. Patients with creatinine clearanceabove 50 ml/min excreted 80 to 100% of thedose given. Patients with decreased creatinineclearances of 30 to 50 ml/min had proportion-

PS AERUGINOSA

P. MIflABILIS -13

MEAN PEAK SERUM LEVELSMEAN PEAK SERUM LEVELS

F* * 0i;"400 MEAN URINE LEVELS

MEAN TROUGH SERUM LEVELSo* so

* * : *..s.:*000.12 0.25 O.S I 2 4 s 16 32 64 12S 2S0 S00

NETILMICIN mcgiml

FIG. 1. Relation of in vitro susceptibilities to meanpeak and trough serum levels and mean urine levels.Dots within the shaded areas represent MICs of in-dividual isolates from study patients. The range ofMICs of other clinical laboratory isolates is repre-sented by the bars. The numbers alongside the barsindicate the number of clinical laboratory strainstested.

VOL. 13, 1978

E.COLi

OTHERS

172 PANWALKER ET AL.

ately decreased netilmicin urine excretion of 30to 80%. There was no measurement of netilmicinexcretion in patients with creatinine clearancesof less than 30 ml/min.The results of treatment are shown in Table

I MAKA(23) ~TROUGH

10

a

4

2

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00

0

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** +0

0

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ANTIMICROB. AGENTS CHEMOTHER.

1. The patients are categorized according to thepresence of bacteremia, tissue infection, or uri-nary tract infection.Bacteremia. Excluding one patient with

Bacteroides fragilis bacteremia (discussed be-low), 9 of the 27 patients had bacteremic disease.Five had gram-negative rod bacteremia from a

urinary portal, one had streptococcal endocar-ditis, one had disseminated gonococcemia, andthe source of gram-negative rod sepsis was in-determinate in the remaining two patients. Allbacteremic patients were clinically and bacteri-ologically cured. Although netilmicin may havebeen synergistic with penicillin in the patientwith streptococcal endocarditis, it is possiblethat penicillin may have cured the infectionalone.

Illustrative cases. (i) Bacteremia withgram-negative bacilli. (a) LM. A 38-year-oldpatient with chronic myelogenous leukemia hadhad klebsiella bacteremia intermittently for 6

T I12

4-~~~~~~~~~-4-5 6.0 7. 4.5 0 7.5

mglkgkay

FIG. 2. Peak and trough serum levels achieved inpatients with serum creatinines less than 2.0 mg/dlreceiving netilmicin doses of 4.5, 6.0, or 7.5 mg/kgper day intramuscularly. The bars indicate medianserum levels at each defined dose.

OPEAK SERM LEVEL

*TROUGH SERUM LEVEL

II0

I i'2 4-0J10 t S

-20 40 60 so 100 12CrSgkdne CMaranoe mI/nbn

FIG. 3. Maintenance (more than 3 days) peak andtrough serum levels compared to simultaneous cre-atinine clearances. Vertical bars connect peak andtrough serum levels of individual patients.

TABLE 1. Site of infection and bacteriological response to treatmentBacteremia Tisue infectionsa Urinary tract infections'

Eradication of initial

Etiology strainCure Failure Cure Failure Failure or

Cure-treat New in relapsenat- fection

E. coli 4 0 1 1 4 0 0Klebsiella-Enterobacter 2 0 2 0 7 3 0P. mirabilis 1 0 1 0 2 1 0Pseudomonas 1 0 2 0 0Other 2 0

a SiX isolates were obtained from four patients: E. coli and Klebsiella and KlebsielUa and P. mirabilis werepresent in two of the patients.

b Fifteen pretreatment isolates were obtained from 12 patients (P. mirabilis and P. aeruginosa, E. coli andKlebsiella, and E. cloacae and E. coli were obtained from three of these patients). Superinfections orreinfections were caused by Candida species (two patients), P. rettgeri, and Pseudomonas maltophilia (onepatient each).

t

0

0

II 0

VOL. 13, 1978

months with relapses following gentamicin/cephalothin treatment. Bacteremia was eradi-cated by netilmicin treatment and the patientimproved clinically. However, a lung infiltrateand pleural effusion developed while the patientwas receiving netilmicin. It subsided during sub-sequent treatment with chloramphenicol.

(b) RS. Shock and enterobacter bacteremia,without an identifiable portal of entry, occurredin a 52-year-old female in the hospital becauseof a myocardial infarction. There were multipleepisodes of arrhythmias, and the patient re-quired mechanical ventilation. After treatmentwith netilmicin, her condition improved rapidly,with clearing of the bacteremia, and she wasdischarged.

(ii) Disseminated gonococcemia: DV. A22-year-old female, with chronic idiopathic liverdisease and penicillin allergy, presented with aclinical picture of gram-negative sepsis, whichincluded fever, chills, and hypotension. After 5days of netilmicin therapy, the initial blood cul-tures grew Neisseria gonorrhoeae. Significantclinical improvement had already occurred, andthe infection was eradicated after 2 weeks ofnetilmicin.Tissue infections. Six organi were iso-

lated from four patients with severe tissue infec-tions.

(i) Pneumonia. Two patients with pneu-monia were cured. One with E. coli pneumoniareceived concomitant ampicillin therapy. Inspite of clinical cure, the E. coli persisted in thesputum cultured after completion of therapy.

(ii) Wound infection. One patient had asevere abdominal wall wound infection afterrenal transplantation. A gentamicin-resistantstrain of P. aeruginosa (MIC >500,ug/ml) wasrecovered in pure culture; the isolate was sus-ceptible to 16 ug of netilmicin per ml. The or-ganism was eliminated from the wound within72 h; however, because of persistent fever, car-benicillin (which in vitro was synergistic withnetilmicin) was added. Resolution of fever oc-curred in 3 weeks with combined therapy.

(iii) Osteomyelitis. A patient with osteomye-litis of the right hip and acetabulum had severesoft-tissue infection in the gluteal region second-ary to deep infected decubiti and bacteremiawith B. fragilis. Proteus mirabilis and klebsiellawere isolated repeatedly from the wounds andsurgically excised bone. The patient receivedtreatment with netilmicin and clindamycin for6 weeks. Clinical improvement and a bacterio-logical cure were attained, but a netilmicin-re-sistant strain of Acinetobacter calcoaceticusvar. anitratus (MIC, 500 ug/ml) colonized thehealing wound.Nonbacteremic urinary tract infections.


Fifteen organisms were isolated from the urinecultures of 12 patients. Ten of the 12 patientshad a febrile illness; 2 others who were asymp-tomatic had infected renal allografts. In one ofthe latter, the infection was caused by a genta-micin-resistant strain of Enterobacter cloacae.Fluorescent stains for the demonstration of an-tibody-coated bacteria in urine were positive insix of the eight patients studied. Treatment withnetilmicin eradicated the infecting strains in allpatients, and no relapses had occurred 4 weeksafter the completion of treatment. During thisperiod there were two superinfections withstrains of yeast and two bacterial reinfections.Three patients with a clinical diagnosis of acutepyelonephritis are not shown in Table 1. Thesymptoms in these patients disappeared duringtreatment.

Ototoxicity. Only one patient complained oftinnitus with dizziness, which was transient andnot associated with ataxia, nystagmus, or audi-ometric changes. Of 21 patients who had audio-metric studies, one had ototoxicity. As shownby audiometry, this was partially reversible anddid not involve hearing loss of tones in theconversational range. The patient was 42 yearsold, had paraplegia, and was treated with bothnetilmicin and clindamycin for bacteremia withshock. The treatment lasted 42 days and wasnot associated with high peak levels of netilmicin(range, 5.8 to 8.3 .g/ml), although the troughlevels rose from 2.4 ug/ml on day 4 (on 7.5mg/kg per day) to 4.9 ,ug/ml on day 30 (on 4.5mg/kg per day). There was no history of pre-vious aminoglycoside or diuretic treatment.The absence of ototoxicity in two of the pa-

tients is notable. One, who was undergoing he-modialysis, developed peak levels as high as 36,ug/ml (range, 15 to 36 jig/ml) and trough levelsas high as 24 .Lg/ml (range, 10 to 24 ,ug/ml) overa treatment period of 3 weeks. These high levelswere deemed necessary for cure in an immuno-suppressed patient with a moderately resistantorganism. No evidence of toxicity appeared inthe audiogram performed on day 16 of treat-ment. Another patient, who developed nephro-toxicity, had high peak and trough levels, pro-longed treatment, and previously documentedgentamicin-related hearing lo0s. No worseningof the initially abnormal audiogram was dem-onstrated.Nephrotoxicity. Twenty-five patients had

either serum creatinine or creatinine clearancedata adequate for analysis of nephrotoxicity. Bypreviously defined criteria, 4 of 25 patients(16%) had significant changes in renal functionduring therapy. In two of these patients theelevation in serum creatinine was evaluated asprobably related to the drug therapy (definite


toxicity) and in the other two patients as possibledrug-related toxicity. Two patients with toxicitywere male (from a total of seven) and two werefemale (from a total of 18). Three of the fourpatients were bacteremic, but none were inshock at any time. Three of the four patientshad underlying renal disease (urethral stricture,papillary necrosis, and/or pyelonephritis), andtwo had received other aminoglycosides withinthe past year. Although not statistically signifi-cant, the patients with nephrotoxicity in com-parison to nontoxic patients were older, receivedtreatment for longer periods of time, and re-ceived a larger total amount of netilmicin, butthe mean daily dose was not different in thetwo groups. There were no differences in peakor trough serum levels achieved in the first 72h. In the maintenance period, however, both thepeak and trough levels were higher in the toxicpatients (P = 0.002 and 0.047, respectively). Theelevations in serum creatinine were noted duringdays 3 to 5 of therapy in two of the patients,and the elevated serum levels could have beeneither secondary to worsening renal function ora cause for the toxicity. One patient developedtoxicity after 4 weeks of treatment when thedose of netilmicin was increased. The toxicitywas transient in all patients, with serum creati-nine retuning to pretreatment levels soon afterdiscontinuation of therapy.Elevations of alkaline phosphatase. Nine

of 21 patients (43%) who had serial measure-ments of SGOT and alkaline phosphatase ade-quate for analysis had an increase in serumalkaline phosphatase ranging from 23 to 209%as compared to their initial measurement, at-taining pathological levels in all but one. How-ever, there was no clinical evidence of hepato-biliary toxicity. No sequelae or persistent abnor-malities were recognized after the treatment wasstopped. In five of six patients with electropho-retic fractionation of the serum alkaline phos-phatase, the liver band was the predominantone and was increased above normal. In theremaining patient, bands characteristic of bothintestinal and liver alkaline phosphatase werepresent. Elevations of SGOT accompanied therise in alkaline phosphatase in three of the ninepatients and were also seen in two patients withno rise. Underlying liver disease (cirrhosis, hep-atitis) was unrelated to enzyme elevations, beingpresent in three patients with alkaline phospha-tase rise and four patients showing no rise. Threeof the four nephrotoxic patients also developeda significant elevation of alkaline phosphatase.The patients with drug-related elevations of al-kaline phosphatase were older, had a longerduration of therapy, and received a higher total


and mean daily dose; however, none of thesedifferences were statistically significant. Meanpeak serum levels after 3 days were significantlyhigher (P = 0.02) in patients with elevated al-kaline phosphatase than in the others; troughlevels were also increased, but the differencewas not significant (P = 0.2). After exclusion ofthe nephrotoxic patients, peak and trough serumlevels after day 3 remained higher for the groupwith elevated alkaline phosphatase.

DISCUSSIONFactors that dictate the choice of an amino-

glycoside antibiotic include favorable clinicaland experimental therapeutic experience, thespectrum of antibacterial activity, prevalence ofresistant strains, and the toxicity of the drug.The therapeutic results obtained in this inves-tigation are remarkably good. Nearly all of theinfections were cured, although the underlyingdiseases were serious in many of the patients.In the four instances where other antibioticswere used in conjunction with netilmicin, syn-ergy was either demonstrated or expected. Inthese patients, cure cannot be attributed to ne-tilmicin alone. In a controlled study, the thera-peutic efficacy of gentamicin and amikacin ap-proached 80% (21). Thus, the efficacy of netil-micin appears to be at least as good as that withother effective aminoglycoside antibiotics.The increased in vitro activity of netilmicin

can be considered to increase its therapeuticpotential, but this advantage, if any, cannot beevaluated in this trial. Two of the isolates frompatients in the series were resistant to gentami-cin and susceptible to netilmicin. Thus, the abil-ity of netilmicin to withstand inactivation bysome of the most common bacterial enzymesassociated with gentamicin-resistant strainsbroadens its base of activity, although not ascompletely in this respect as amikacin (4, 16).This property should decrease the ease withwhich resistant strains can emerge during theselective pressure of antibiotic administration topatients.A principal limiting factor in the treatment

of serious gram-negative bacterial infectionswith aminoglycoside antibiotics is the narrowratio between therapeutic and toxic serumlevels. Peak serum concentrations of gentamicinbelow 4 ,ug/ml have been associated with per-sistent bacteremia with P. aeruginosa, causinga greater fatality rate than when higher druglevels were achieved (9). Peak postinjectionlevels of gentamicin above 8 ,ug/ml produce anincreased risk of ototoxicity and possibly alsonephrotoxicity (8). A dose of 6 mg of netilmi-

VOL. 13, 1978

cin/kg per day produced peak serum levelsabove 4 and below 10 ,ug/ml, with a medianlevel of 7 and a trough level less than 2 ,ug/mlin all but a few patients. This may be ideal forthe treatment of serious infections other thanthose of the urinary tract, which may not requiresuch high plasma levels.The almost complete freedom from ototoxic-

ity after netilmicin administration to animals isimportant, if it can be confirmed in humans(20). Of particular interest is the absence of anydiscernible ototoxicity in two patients who de-veloped extraordinarily high serum levely of ne-tilmicin for periods of 2 to 3 weeks. On the otherhand, the partially reversible unilateral ototox-icity found in one patient with usual therapeuticlevels indicates that ototoxicity occurring in thecourse of treatment of serious illness and com-bination with other drugs is not entirely predict-able and not related only to the plasma concen-tration of drug.

Nephrotoxicity was considered definitely re-lated to netilmicin in two patients (8%) andpossibly drug related in two others. This is com-parable to the rate of toxicity noted with ami-kacin (17%) (14) and gentamicin (2 to 10%) (7).Thus, the animal data showing netilmicin to befar less nephrotoxic than gentamicin and ami-kacin are not confirmed in this investigation.Perhaps the animal studies are not relevant tohumans, but more likely is the greater impor-tance of other factors that may predispose pa-tients to drug-induced renal damage. As in pre-vious experience, the host factors found to beof particular importance in the development ofnephrotoxicity were prior aminoglycoside ther-apy, increased age, and underlying renal diseaseand, among the drug factors, higher serum levels,longer duration of therapy, and a larger totaldose.A significant rise in hepatic enzymes has not

been recognized with most ofthe aminoglycosideantibiotics. In this experience, however, eleva-tion of serum alkaline phosphatase occurred in43% of the patients tested and was of hepaticorigin in all patients whose sera were fraction-ated. Failure of the level of SGOT to increasein parallel with the alkaline phosphatase mightsuggest the abnormality is in the biliary ducts,rather than the liver parenchyma. Three of thenine patients with elevated levels of alkalinephosphatase also had nephrotoxicity; thus, theeffect may have factors in common. Patientswith enzyme rise were older, received a higherdose of netilmicin, and had higher trough serumlevels; however, none of these were statisticallysignificant. The peak serum level of drug mea-sured after 3 days of therapy was consistently


higher (P = 0.02). This further relates the alter-ation directly to netilmicin treatment, but sinceno sequelae or persistent abnormalities wererecognized, its importance is unknown.

Results of this study show that netilmicin isan effective antibiotic. The advantages of in-creased bactericidal activity and reduced risk ofototoxicity with prolonged therapy and highlevels recommend it as an improvement overgentamicin in the treatment of severe gram-neg-ative bacterial infections. Nevertheless, the po-tential for ototoxicity and nephrotoxicity re-mains appreciable. In addition, the associationof netilmicin in the production of increased se-rum levels of alkaline phosphatase in a highproportion of patients is a new finding that re-quires further evaluation.

ACKNOWLEDGMEENTSWe thank the following persons who assisted in this inves-

tigation: Mohammed Ghafoor, Thomas Gifford, Francois La-mothe, and the House Staff of the University Hospital. Wealso thank Michael Siefert and Maurice Joseph for assistancein interpretation of audiometric data and Carolyn Lewis andChris Enriquez for typing the manuscript.

This work was supported by grants from the Schering-Plough Research Division, which also provided netilmicin.

LTERATURE CITED1. Briedis, D. J., and H. G. Robson. 1976. Comparative

activity of netilmicin, gentamicin, amikacin, and tobra-mycin against Pseudomonas aeruginosa and Entero-bacteriaceae. Antimicrob. Agents Chemother.10:592-597.

2. Brown, K. N., J. Benedictson, and S. Swanby. 1976.In vitro comparison of gentamicin, tobramycin, sisomi-cin, and netilmicin. Antimicrob. Agents Chemother.10:768-769.

3. Dhawan, V., E. Marso, W. J. Martin, and L. S. Young.1977. In vitro studies with netilmicin compared withamikacin, gentamicin, and tobramycin. Antimicrob.Agents Chemother. 11:64-73.

4. Dowding, J., and J. Davies. 1975. Mechanisms andorigins of plasmid-determined antibiotic resistance, p.179-186. In D. Schlesinger (ed.), Microbiology-1974.American Society for Microbiology, Washington, D.C.

5. Flournoy, D. J. 1976. Sisomicin versus netilmicin: invitro susceptibility testing. Antimicrob. Agents Chem-other. 10:864-865.

6. Fu, K. P., and H. C. Neu. 1976. In vitro study of netil-micin compared with other aminoglycosides. Antimi-crob. Agents Chemother. 10:526-534.

7. Hewitt, W. L. 1974. Gentamicin: toxicity in perspective.Postgrad. Med. J. 50(Suppl. 7):55-59.

8. Jackson, G. G., and G. Arcieri. 1971. Ototoxicity ofgentamicin in man: a survey and controlled analysis ofclinical experience in the United States. J. Infect. Dis.124(Suppl.) :S130-S137.

9. Jackson, G. G., and L Riff. 1971. Pseudomonas bacter-emia: pharmacologic and other basis for failure of treat-ment with gentamicin. J. Infect. Dis. 124(Suppl.):185-191.

10. Kabins, S. A., C. Nathan, and S. Cohen. 1976. In vitrocomparison of netilmicin, a semisynthetic derivative ofsisomicin, and four other aminoglycoside antibiotics.Antimicrob. Agents Chemother. 10:139-145.

11. Kantor, R. J., and C. W. Norden. 1977. In vitro activity


of netilmicin, gentamicin, and amikacin. Antimicrob.Agents Chemother. 11:126-131.

12. Luft, F. C., M. N. Yum, and S. A. Kilit. 1976. Compar-ative nephrotoxicities of netilmicin and gentamicin. An-timicrob. Agents Chemother. 10:84649.

13. Meyer, R. D., L L Kraus, and K. A. Palecznlk 1976.In vitro susceptibility of gentamicin-resistant Entero-bacteriaceae and Pseudomonas aeruginosa to netil-micin and selected aminoglycoside antibiotics. Antimi-crob. Agents Chemother. 10:677-681.

14. Meyer, R. D., R. P. Lewis, E. D. Carmalt, et al. 1975.Amikacin therapy for serious Gram negative bacillaryinfections. Ann. Intern. Med. 83:790-800.

15. Meyers, B. M., and S. Z. Hhrschman. 1977. Antimicro-bial activity in vitro of netimicin and comparison withsisomicin, gentamicin, and tobramycin. Antimicrob.Agents Chemother. 11:118-121.

16. Miler, G. H., G. Arcieri, M. J. Weinstein, and J. A.Waltz. 1976. Biological activity of netilmicin, a broad-spectrum semisynthetic aminoglycoide antibiotic. An-timicrob. Agents Chemother. 10:827436.

17. Philips, L, A. Smith, and K. Shannon. 1977. Antibac-terial activity of netilmicin, a new aminoglycoside an-


tibiotic, compared with that of gentamicin. Antimicrob.Agents Chemother. 11:402-406.

18. Rahal, J. J., M. S. Simberkoff, K. Kagan# and N. H.Moldover. 1976. Bactericidal efficacy of SCH 20669and amikacin against gentamicin-sensitive and -resist-ant organims. Antimicrob. Agents Chemother.9:5956-599.

19. Riff, L, and G. Morewchi. 1977. Netilmicin and genta-nicin: comparative pharmacology in humans. Antimi-crob. Agents Chemother. 11:609-614.

20. Schering Corporation. 1977. Information material forinvestigational drug netilmicin. Scherng Corp., Bloom-field, N.J.

21. Smith, C. R. V., K. L Baughman, C. L Edwards, J.F. Rogers, and P. S. Letman 1977. Controlled com-parison of amikacin and gentamicin. N. Engl. J. Med.296:349-353.

22. Smith, J. A., J. R. Morgan, and KL Mogyoros. 1977.In vitro activity of netilmicin. Antimicrob. AgentsChemother. 11:362-364.

23. Watana-unakorn, C. 1976. Comparative in vitro activityof SCH 20656, netilmicin, gentamicin, and tobramycin.Antimicrob. Agents Chemother. 10:382-383.

Documents

Netilmicin Clinical Efficacy, Tolerance, And Toxicity