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• To study the effectiveness of collagen shields containing tobramycin sulfate in the treatment of Pseudomonas keratitis, rabbits were infected via an intrastromal injection of Pseudomonas aeruginosa and treated 22 hours later with either collagen corneal shields rehydrated in 4% tobramycin and applied to the cornea or 4% tobramycin drops. Bacterial killing was quantitated by culturing corneal homogenates and calculating the number of viable bacteria (colony-forming units) per cornea. Corneas receiving shields rehydrated in 4% tobramycin and applied for four hours demonstrated significantly reduced numbers of bacteria compared with untreated control corneas. The collagen shields were as effective in reducing the number of viable bacteria per cornea as 4% tobramycin drops applied every 30 minutes over a four-hour period. Over a nine-hour treatment period, the addition of four drops of 4% tobramycin to shields in situ was as effective as exchange with a new shield rehydrated in 4% tobramycin. These results suggest that collagen shields rehydrated in a water-soluble antibiotic such as tobramycin may be an effective and convenient mode of therapy for Pseudomonas keratitis.

The ototoxicities of tobramycin sulfate and gentamicin sulfate were investigated in guinea pigs under conditions of normal, increased, and decreased hydration. Increased hydration was associated with no decline in the amplitude of the cochlear microphonics, a lesser decline in the eighth nerve action potentials and lesser damage to the organ of Corti. Decreased hydration was associated with an increase in the threshold of the cochlear microphonics and the eighth nerve action potentials, a decline in the amplitude of the cochlear microphonics, a greater decline in the eighth nerve action potentials, and greater damage to the organ of Corti. Tobramycin sulfate was substantially less toxic than gentamicin sulfate with normal, increased and decreased hydration. These findings suggest the preferential use of tobramycin sulfate for patients with normal renal function, and especially patients with renal impairment.

• Two cases of osteolytic lesion of the sternum were caused byPseudomonas aeruginosa. Both were in heroin addicts, and both occurred as a delayed reaction to injury in an automobile accident. Bony curettage and appropriate antibiotic therapy were sufficient for diagnosis and cure. Tobramycin sulfate (3 mg/kg/day), a new aminoglycoside, was successfully used in both instances. Excision of the sternum was not necessary. (Arch Surg111:776-778, 1976)

• A prospective randomized study compared the use of moxalactam disodium vs clindamycin phosphate and tobramycin sulfate for treatment of 190 patients with penetrating abdominal trauma. Twenty-seven patients were disqualified because of early death or failure to follow the protocol. The patients in each group were comparable regarding the cause and severity of injury. No significant difference was seen in the incidence of intra-abdominal infection between the moxalactam-treated group (13%) and the clindamycin- and tobramycin-treated group (9%). The intra-abdominal infection rate in patients with colon injuries (21%) was significantly increased when compared with the patients without colon injuries (6%), but the antibiotic regimen did not significantly change the infection rate. No evidence of bleeding problems from moxalactam were noted. Changes in prothrombin and partial thromboplastin times appeared to be related to shock rather than the use of moxalactam. The most severe coagulopathies occurred prior to moxalactam therapy and were seen only in those patients who had shock requiring 10 or more units of blood. Moxalactam is as effective as combination (clindamycin and tobramycin) antimicrobial therapy in patients with penetrating abdominal trauma. { Arch Surg 1986;121:153-156)

Fifty-four healthy guinea pigs were studied histologically for evaluation of Tobramycin sulfate ototoxicity. They were treated with 50, 100, 150 and 200 mg/kg/day under different schedules. Loss of hair cells occurred when dosage of 1,200 mg/kg was reached. Animals receiving 700 mg/kg were without damage to the inner ear. Outer hair cell loss occurred first in the basal turn, spreading upward. Inner hair cell loss began in the apical turn, progressing downward. When a total dose of 1,400 mg/kg was reached by (two) different schedules the higher daily dose produced about twice the hair cell loss; therefore, the ototoxic effect depends on the total dose but even more on the increased blood concentration.

A study of intravitreal injection of tobramycin sulfate in the treatment of experimental Pseudomonas aeruginosa endophthalmitis in rabbits resulted in the following findings: (1) A dose of 750 μg per 0.1 ml was nontoxic to ocular structures. (2) 500 μg of tobramycin sulfate remained bactericidal in both aqueous and vitreous humors for at least 96 hours. (3) Eyes cleared if treated with intravitreal injection of 500 μg tobramycin sulfate seven hours after bacterial inoculation, while only 2 of 5 eyes treated ten hours after inoculation showed complete clearing. (4) Systemic and subconjunctival administration of antibiotic failed to eradicate infection in 10 eyes.

• Antibiotic therapy of experimental Pseudomonas keratitis was evaluated quantitatively by determining numbers of viable bacteria in the cornea of guinea pigs. Topically applied carbenicillin disodium, gentamicin sulfate, and tobramycin sulfate were often significantly more effective than topically applied polymyxin B sulfate. Intramuscular therapy with tobramycin was as effective as topical therapy, and the results exhibited less variability. Topical tobramycin every 30 minutes was significantly more effective than topical therapy every 60 minutes. No combination of antibiotics was significantly better than a single effective drug. The concentration of tobramycin in the aqueous correlated more closely to therapeutic efficacy than did the concentration in the cornea. Although all antibiotics reduced numbers of bacteria in the cornea by more than 99% in the first 24 hours of therapy, none was able to sterilize the cornea in four additional days of continuous therapy. Persistence of organisms despite apparently adequate topical therapy may explain some reported cases of relapse in humans. ( Arch Ophthalmol 95:1638-1643, 1977)

The stability and compatibility of clindamycin phosphate admixed separately with gentamicin sulfate, tobramycin sulfate, and amikacin sulfate in polypropylene syringes under specific storage conditions were studied. In duplicate syringes, clindamycin phosphate 900 mg was admixed with sterile NaCl 0.9% 1 ml and with either gentamicin sulfate 120 mg, tobramycin sulfate 120 mg, or amikacin sulfate 750 mg. In duplicate polypropylene syringes, control solutions of clindamycin phosphate and each aminoglycoside were prepared separately and stored under the same conditions. The clindamycin control consisted of clindamycin phosphate 900 mg in 6 ml. The gentamicin and tobramycin controls consisted of gentamicin sulfate and tobramycin sulfate 120 mg in 3 ml plus 1 ml of sterile NaCl 0.9%. The amikacin control consisted of amikacin sulfate 750 mg in 3 ml plus 1 ml of sterile NaCl 0.9%. Drug concentrations were determined at the time of preparation and 1, 4, 8, 12, 24, and 48 hours thereafter. Aminoglycosides were assayed by fluorescence polarization immunoassay and clindamycin was assayed by high performance liquid chromatography. Visual inspections and pH determinations of each combination and control solution were performed at each assay time. For the clindamycin, gentamicin, tobramycin, and amikacin control solutions, changes in concentration were within ten percent of the original concentration. Concentrations of clindamycin and gentamicin when admixed together also remained within ten percent of the original concentration. Similar results were found with concentrations of clindamycin and amikacin when admixed together. Tobramycin and clindamycin formed a lasting precipitate upon initial contact when admixed under the study conditions.

Tobramycin sulfate, a new bactericidal aminoglycoside antibiotic, has been evaluated in 3,506 patients. Its in vitro activity is similar to that of other aminoglycoside antibiotics, except that it is more active against Pseudomonas aeruginosa. Clincal studies have shown that tobramycin sulfate is well tolerated and effective in the treatment of the infections listed below when they are caused by susceptible gram-negative organisms and by staphylococci: infections of the respiratory tract (including cystic fibrosis), central nervous system, skin, soft tissue, and bone (including burns); urinary tract and intraabdominal infections; and septicemia. The overall response was satisfactory in greater than 86% of the patients. Drug-related adverse effects were reported in 3.9% of the patients, and included reactions in the nervous system in 0.6% and in the kidney in 1.5%.

We evaluated several therapeutic modifications in an attempt to improve efficacy of topical therapy with tobramycin of experimental Pseudomonas keratitis in guinea pigs. Removal of corneal epithelium enhanced efficacy of topical therapy with 0.3 mg/ml and 3 mg/ml tobramycin sulfate but did not influence therapy with 40 mg/ml or 400 mg/ml tobramycin. The highest concentration of antibiotic was the most effective; 7 of 12 infected corneas treated with 400 mg/ml tobramycin were sterile in 48 hours. Therapy begun soon after the infection was established, when there were relatively few organisms present, was more effective than therapy begun later, when there were many more bacteria in the cornea. Our results are consistent with a basic therapeutic concept. The most effective regimen is one that achieves the highest safe concentration of antibiotic at the site of infection as early in the course of infection as possible.

• The effects of antibiotics and other commonly used medications on the human polymorphonuclear neutrophil leukocytes' (PMNs) nicotinamide-adenine dinucleotide phosphatereduced (NADPH) oxidase activity have been investigated in vitro. Five antibiotics (penicillin G sodium, cefamandole nafate, metronidazole hydrochloride, clindamycin phosphate, and tobramycin sulfate, and a triple combination of penicillin G sodium-metronidazole hydrochloride-tobramycin sulfate) and two sedatives (morphine sulfate and diazepam) were incubated with normal human PMNs at therapeutic, infratherapeutic, and supratherapeutic drug levels. The superoxide dismutase-inhibitable, NADPH-dependent reduction of cytochrome C in the PMNs was studied after stimulation with formyl-methionyl-leucine-phenylalanine. Tobramycin sulfate and the triple combination of penicillin G sodium—metronidazole hydrochloride-tobramycin sulfate significantly reduced the NADPH oxidase activity at all dosages studied. Clindamycin phosphate, morphine sulfate, and diazepam also showed significant reduction at therapeutic and supratherapeutic concentrations. Penicillin G sodium, cefamandole nafate, and metronidazole hydrochloride did not cause a decrease in enzyme activity at any levels tested. We conclude that NADPH oxidase activity can be adversely affected by the circulating levels of common antibiotics and sedatives. ( Arch Surg 1986;121:73-76)

BACKGROUND: Bone graft substitute such as calcium sulfate are frequently used as carrier material for local antimicrobial therapy in orthopedic surgery. This study aimed to assess the systemic absorption and disposition of tobramycin in patients treated with a tobramycin-laden bone graft substitute (Osteoset® T). METHODS: Nine blood samples were taken from 12 patients over 10 days after Osteoset® T surgical implantation. Tobramycin concentration was measured by fluorescence polarization. Population pharmacokinetic analysis was performed using NONMEM to assess the average value and variability (CV) of pharmacokinetic parameters. Bioavailability (F) was assessed by equating clearance (CL) with creatinine clearance (Cockcroft CLCr). Based on the final model, simulations with various doses and renal function levels were performed. (ClinicalTrials.gov number, NCT01938417). RESULTS: The patients were 52 +/- 20 years old, their mean body weight was 73 +/- 17 kg and their mean CLCr was 119 +/- 55 mL/min. Either 10 g or 20 g Osteoset® T with 4% tobramycin sulfate was implanted in various sites. Concentration profiles remained low and consistent with absorption rate-limited first-order release, while showing important variability. With CL equated to CLCr, mean absorption rate constant (ka) was 0.06 h-1, F was 63% or 32% (CV 74%) for 10 and 20 g Osteoset® T respectively, and volume of distribution (V) was 16.6 L (CV 89%). Simulations predicted sustained high, potentially toxic concentrations with 10 g, 30 g and 50 g Osteoset® T for CLCr values below 10, 20 and 30 mL/min, respectively. CONCLUSIONS: Osteoset® T does not raise toxicity concerns in subjects without significant renal failure. The risk/benefit ratio might turn unfavorable in case of severe renal failure, even after standard dose implantation.

The intraocular penetration of tobramycin sulfate, a new aminoglycoside antibiotic, was evaluated in rabbits following subconjunctival injection. The mean tobramycin sulfate concentration in the aqueous humor 60 minutes after a single 5-mg dose was 5.5 mug/ml, as compared to a mean concentration of 6.7 mug/ml following a single 10-mg dose. These levels exceed the minimal inhibitory concentration (MIC) for most Pseudomonas species and a variety of other Gram-negative bacilli recovered from clinical infection. No anterior segment changes that may be attributed to the antibiotic could be demonstrated in the injected eye.

• A Pseudomonas-caused corneal ulcer developed in a 44-year-old man with severe facial and upper torso thermal burns while in the hospital burn unit. The infecting strain was resistant to most antibiotics, including gentamicin sulfate and tobramycin sulfate. Treatment with topical and parenteral amikacin sulfate resulted in rapid healing. To our knowledge, there have been no reports of the use of amikacin for corneal ulcer. The successful healing in this case suggests that the use of amikacin should be considered in the treatment of corneal ulceration when it is suspected that the pathogen is a Pseudomonas strain resistant to gentamicin and other commonly used antibiotics.

Tobramycin sulfate is a bactericidal aminoglycoside antibiotic which in animal studies has been shown to have lower acute toxicity and lower nephrotoxicity than gentamicin (1,2). Tobramycin has been shown to have more activity in vitro against Pseudomonas sp. than other aminoglycoside antibiotics (3,4). Tobramycin is excreted unchanged in the urine and assayable blood levels are present for at least eight hours. Studies in patients with renal failure showed that the serum half-life was directly related to the degree of renal impairment and that reduced doses were necessary. This antibiotic was found to be effective against infections due to susceptible organisms in the genitourinary system- Pseudomonas sp., Esch. coli, the Klebsiella-Enterobacter-Serratia group, indole-positive and indole-negative Proteus sp., staphylococci and group D streptococci. Early clinical studies showed that Tobramycin was successful in eradicating infections with Pseudomonas sp. which had prior unsuccessful therapy with gentamicin and/or carbenicillin.

Inactivation of tobramycin sulfate by ticarcillin disodium was observed in a patient with impaired renal function. Tobramycin elimination half-life was seven hours with concurrent ticarcillin therapy but 35 hours without ticarcillin therapy. The magnitude of change cannot be attributed to changing renal function or tobramycin accumulation. The present case demonstrates that in vivo inactivation of tobramycin by ticarcillin can substantially increase the overall tobramycin elimination rate in patients with severe renal failure; however, in patients with normal renal function such inactivation is predicted to cause little change in overall tobramycin elimination rate. ( JAMA 1982;247:658-659)

To the Editor.— The prospective study of the clinical nephrotoxicity of tobramycin sulfate and gentamicin sulfate reported by Gerald D. Kumin, MD (1980;244:1808), brings further attention to the magnitude of the problem of aminoglycoside-related renal failure and presents data indicative of a substantially higher incidence of gentamicin-associated renal dysfunction in comparison with that of tobramycin in groups receiving standard clinical daily doses of these drugs. However, despite the admission of the difficulty in designing controlled clinical studies in seriously ill patients, 62 patients were treated with 2 to 5 mg/kg/day of gentamicin sulfate or tobramycin sulfate for a variety of serious infections. No serum aminoglycoside levels are reported, and no data are presented to allow conclusions regarding possible differences in efficacy of therapy between groups. Yet there is another issue. Riff and Jackson 1 demonstrated that the dosage of gentamicin based on the weight of the patient produced wide variations

TOBRAMYCIN sulfate and a related aminoglycoside, gentamicin sulfate, are valued for their efficacy in treating serious Gram-negative infections despite their narrow therapeutic ratio. 1 Their widespread use is reflected in 1978 projections from demographic and clinical data that estimated that 3.9 million patients received one course of treatment with an aminoglycoside that year. 2 Reports of serious adverse reactions to these drugs have usually described nephrotoxicity or ototoxicity. Though we can find no published description of tobramycin's corticoneuronal toxicity, there are several case reports of acute toxic psychosis with gentamicin. 3,4 These led us to suspect tobramycin as the cause of delirium in the patient described here. Report of a Case The patient was a 66-year-old woman with urinary incontinence. Following radical hysterectomy and radiation therapy for cervical cancer, she had required three surgical procedures for stress urinary incontinence. Intermittent self-catheterization was then offered to relieve the resultant increased residual

Amikacin sulfate, the first semisynthetic aminoglycoside antibiotic introduced in this country, is resistant to the bacterial enzymes that specifically inactivate kanamycin sulfate, gentamicin sulfate, and tobramycin sulfate. This agent is potentially effective, therefore, against many serious infections caused by Gram-negative organisms resistant to other aminoglycosides. It appears to be similar to gentamicin in its in vitro spectrum, in clinical applications, and in the incidence and severity of adverse reactions reported. Like the other drugs in this class, amikacin can cause renal and otic toxic reactions. ( JAMA 238:1547-1550, 1977)

An experimental model of staphylococcal keratitis in guinea pigs was devised that is suitable for quantitative evaluation of therapy. The growth curve in the cornea of a virulent strain of Staphylococcus aureus was determined. The organism multiplied rapidly, reached a peak in about 12 hours, and began to decline in numbers after three days. Infections were relatively resistant to therapy begun 24 hours after infection was established. Treatment started earlier when fewer bacteria were present was more effective than treatment begun later. Treatment begun at the time of infection, which might be considered prophylaxis, was highly effective. When treatment was begun eight hours after infection, tobramycin sulfate and gentamicin sulfate solutions administered topically in doses of 20 mg/ml were more effective than topical bacitracin, erythromycin, clindamycin phosphate, or a solution containing polymyxin B sulfate, neomycin sulfate, and gramicidin. Bacitracin and erythromycin ointments were ineffective.

Gram-negative bacillary meningitis is a serious threat to patients with head trauma or altered immune systems, or those who have had neurosurgical procedures. The aminoglycoside antibiotics administered systemically and into the cerebrospinal fluid (CSF) have proved useful in the treatment of these infections. Intralumbar and parenteral gentamicin sulfate and tobramycin sulfate were administered to an acromegalic woman withKlebsiellameningitis. She had objective evidence of an adhesive arachnoiditis and symptoms of polyradiculitis. Cessation of the aminoglycoside administration resulted in symptomatic improvement, and reinstitution of therapy caused a recurrence of neurologic symptoms. Polyradiculitis may be a complication of the intralumbar administration of aminoglycosides. (JAMA236:1264-1266, 1976)

To the Editor.— The report inThe Journalof "Possible Tobramycin Delirium" by McCartney and colleagues (1982;247:1319) warrants some comments about attributing their patient's delirium to administration of tobramycin sulfate. First, the patient's age (66 years) is a known predisposing factor for delirium in general, and urinary tract infections alone have been known to cause delirium in elderly patients. 1 Second, from the first day of hospitalization, the patient was given a CNS depressant (flurazepam, 30 mg/day), to which were added (sometime during days 5 to 7) two more CNS depressants (diazepam, 5 to 10 mg/day, and codeine, 30 to 120 mg/day); again, in an elderly patient, this combination per se could easily contribute to or worsen delirium. 2 Third, the disappearance of the delirium within 14 hours after discontinuing tobramycin appears to be remarkably rapid, if tobramycin were indeed the main cause. The time course of the delirium resolution

Nearly 3.2 million people in this country receive aminoglycoside antibiotics annually. Gentamicin sulfate and tobramycin sulfate continue to demonstrate ototoxicity and nephrotoxicity in both animal and clinical studies. In this study, 62 patients with confirmed initial normal renal function and treated with 2 to 5 mg/kg/day of gentamicin sulfate or tobramycin sulfate for a minimum of seven days were followed up prospectively for the development of aminoglycoside-related renal failure, defined as at least a one-third reduction in renal function. In these 62 patients, no other causes for renal failure could be identified. Five of 33 (15%) of the tobramycintreated patients and 16 of 29 (55.2%) of the gentamicin-treated patients had renal failure. Thus, gentamicin was associated with renal failure more than three times as often as was tobramycin. ( JAMA 244:1808-1810, 1980)

A combination of tobramycin sulfate and cefamandole nafate was used as initial empiric therapy for the treatment of 71 evaluable febrile (temperature greater than 38.5 degrees C) episodes in 64 (neutrophils, less than 1,000/microL) adult patients with cancer and granulocytopenia. Carbenicillin sodium or ticarcillin disodium was substituted for cefamandole in patients with Pseudomonas infections and in patients in whom the initial regimen was unsuccessful. Twenty-nine episodes were randomized to receive tobramycin by continuous infusion, while 42 were randomized to receive tobramycin by interrupted infusion. Twenty-seven (79%) of the 34 documented infections responded to the initial empiric antibiotic combination, ten (83%) of 12 being given continuous infusion and 17 (77%) of 22 being given interrupted infusion of tobramycin. Nephrotoxic reaction occurred in 7% of patients treated with continuous infusion and 15% treated with interrupted infusion, mostly patients older than 60 years. Tobramycin, by either continuous or interrupted infusion, plus cefamandole is safe and efficacious empiric therapy for infections in patients with cancer and granulocytopenia.

To the Editor. —Aminoglycoside antibiotics are routinely injected subconjunctivally at the conclusion of routine cataract extraction by many cataract surgeons. Both tobramycin sulfate and gentamicin sulfate are highly effective againstStaphylococcusspecies and a broad range of gram-negative pathogens, especiallyPseudomonasspecies.1However, irreversible rapid retinal toxicity may occur if these drugs enter the eye. Report of a Case. —A 58-year-old woman underwent routine extracapsular cataract extraction with posterior chamber intraocular lens implantation in her left eye. A 4-mL retrobulbar injection of equal amounts of 1% xylocaine with epinephrine and 0.75% marcaine and 0.5 mL of hyaluronidase was given preoperatively. The procedure was uneventful and the posterior capsule was noted to be intact. At the conclusion of the procedure, 20 mg of tobramycin was injected subconjunctivally within the superior fornix-based conjunctival flap, thereby ballooning the flap over the corneoscleral wound. On the first postoperative day, a good red reflex

• The efficacy of therapy with cefoxitin sodium plus tobramycin sulfate, with the tobramycin therapy discontinued if no cefoxitin-resistant pathogens grew from appropriate cultures, was compared with clindamycin phosphate plus tobramycin therapy in mixed aerobic/anaerobic intra-abdominal and female pelvic infections. Of 96 evaluable patients, 39 (76%) of 51 randomized to cefoxitin and 38 (84%) of 45 randomized to clindamycin were cured and an additional seven (14%) of 51 and three (6.7%) of 45, respectively, were improved.Bacteroides fragilis"group" was isolated from 44 (54%) of 82 patients with appropriate specimens. Duration of aminoglycoside therapy was significantly shorter in patients randomized to cefoxitin and tobramycin (mean, 4.1±1.8 days vs 7.0±3.2 days). There was a tendency to greater nephrotoxic reactions in patients randomized to clindamycin and tobramycin. We conclude that cefoxitin plus tobramycin with selective early discontinuation of aminoglycoside therapy is an acceptable regimen for the therapy of mixed aerobic/anaerobic infections. (Arch Surg1986;121:891-896)

• To evaluate the cost-effectiveness of cefotaxime sodium at a dosage of 12 g/day vs nafcillin sodium and tobramycin sulfate for the treatment of serious infection, the hospital and physician charges of patients enrolled in a prospective, randomized, clinical trial were analyzed. For 187 patients receiving therapy empirically, mean hospital charges for the interval in which the trial antibiotics were used were $3,550±$1,740 for cefotaxime and $3,160±$1,990 for nafcillin and tobramycin. After adjusting for cost-generating factors, charges for cefotaxime were greater than for nafcillin and tobramycin, but the difference was not significant. For 107 patients with clinically or bacteriologically documented infection, mean charges were $3,980±$1,800 for cefotaxime and $4,170±$1,780 for nafcillin and tobramycin. Adjusted charges did not differ. Incremental charges for cefotaxime per additional response were $1,630 in all patients and -$820 in patients with clinically or bacteriologically documented infections. ( Arch Intern Med 1986;146:1153-1157)

LISTERIA monocytogenes endocarditis is an extremely rare entity with, to our knowledge, only 13 cases reported since 1955.1,2Unlike other cases of listeriosis, endocarditis caused by this organism does not preferentially occur in immunosuppressed patients. To our knowledge, this communication describes the first successfully treated case ofL monocytogenesendocarditis involving a prosthetic heart valve. Also presented are in vitro studies showing synergy with penicillin G potassium and tobramycin sulfate and with other antibiotics that might be useful in the penicillin-allergic patient. Such treatment programs may show greater bactericidal activity and less toxic reaction than those using older aminoglycosides, ie, kanamycin sulfate or streptomycin sulfate. Materials and Methods The blood culture isolates were identified asL monocytogenessince they were catalase-positive, pleomorphic, nonsporing Gram-positive rods. They exhibited a characteristic end-over-end tumbling motility at 20 to 25 °C and a narrow ring of β-hemolysis on blood agar. The minimal inhibitory

• We prospectively compared the efficacy and safety of netilmicin sulfate or tobramycin sulfate in conjunction with piperacillin sodium in 118 immunocompromised patients with presumed severe infections. The two treatment regimens were equally efficacious. Nephrotoxicity occurred in a similar proportion in patients treated with netilmicin and tobramycin 17% vs 11%). Ototoxicity occurred in four (9.5%) of 42 netilmicin and piperacillin and in 12 (22%) of 54 tobramycin and piperacillin—treated patients. Of those evaluated with posttherapy audiograms, three of four netilmicin and piperacillin—treated patients had auditory thresholds return to baseline compared with one of nine tobramycin and piperacillin—treated patients. The number of ≥15-dB increases in auditory threshold as a proportion of total ≥15-dB changes (increases and decreases) was significantly lower in netilmicin and piperacillin— vs tobramycin and piperacillin—treated patients (18 of 78 vs 67 of 115). We conclude that aminoglycoside-associated ototoxicity was less severe and more often reversible with netilmicin than