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Treatment of complicated urinary tract infections with amikacin Comparison of low and high dosage
TREATMENT
OF COMPLICATED
INFECTIONS
WITH AMIKACIN
Comparison LLOYD
URINARY TRACT
of Low and High Dosage
H. HARRISON,
M.D.
From the Department of Urology, Bowman Gray School of Medicine, Winston-Salem, North Carolina
ABSTRACT -A randomized prospective study was carried out comparing the recommended dose of amikacin sulfate (Amikin) (15 mg. Kg.) with a lower dose (7.5 mg. Kg.) in the treatment of complicated urinary tract infections. A total of 50 patients were entered in the study over a period of sixteen months. Bacteriologic results were comparable in both groups. Laboratory values remained normal with the exception of 1 patient in the high-dose group who had renal insufficiency. No evidence of ototoxicity was recorded. Our data indicate that low dosage amikacin sulfate is satisfactory in the treatment of complicated urinary tract infections.
Within the last few years increasing numbers of in vitro gentamicin-resistant bacterial isolates have been reported. r* Many of these organisms are sensitive to amikacin (Amikin),5-8 a new semisynthetic aminoglycoside. At the dosage level now recommended for amikacin, high serum and urine concentrations far exceed the MIC of sensitive isolates. If it is true as proposed by Stamey et a1.g that cure of urinary infection is dependent on urinary antimicrobial concentration and not serum levels, use of lower than recommended doses of amikacin may be as effective in the treatment of those patients with urinary tract infections. In addition, the wellrecognized potentiality for ototoxicity and nephrotoxicity may be considerably lessened. A protocol was designed to compare the recommended dosage of amikacin against a lower dosage in the treatment of patients with complicated urinary tract infections. The randomization of 50 patients into a study program over a total period of sixteen months was carried out, and the results are reported herein. Method Patients were entered into the protocol who met the following criteria as having a compli-
110
cated urinary tract infection: (1) Males with prostatic obstruction secondary either to benign or malignant disease; and (2) males/females having stones, indwelling catheters, anatomic and/or functional changes of the urinary tract. Patients who were likely to receive other antimicrobials concomitantly with amikacin were excluded from the study. Patients were divided into two groups of 25 each. Group I was given high dosage amikacin, 15 mg./Kg./twenty-four hours (intramuscularly divided dose every twelve hours). Group II was given low dosage amikacin, 7.5 mg./Kg./twentyfour hours (intramuscularly divided dose every twelve hours). Amikacin dosage (Groups I and II) was adjusted in patients with renal impairment. The dosage interval was calculated by multiplying the serum creatinine by 9. Bacteriologic studies Two midstream clean-catch voided or catheterized specimens growing greater than lo5 organisms per milliliter were obtained. Urine cultures were carried out at forty-eight to seventy-two hours during therapy, on completion of therapy, and one week and four to six weeks after end of therapy. If cultures were
UROLOGY
/
AUGUST
1977
I
VOLUME
X, NUMBER
2
positive at any time during the course of treatment, this was considered an end point, and the patient was placed on another more suitable antibiotic. All bacteriologic isolates were identified by the standard method and tested with single disk sensitivities. lo Isolates were uniformly sensitive to the IO+g. disk* of amikacin. Tube dilution studies for MIC (minimal inhibitory concentration) were performed on all isolates to confirm sensitivity. At midtherapy, after the first dose, a 0 to 6hour sample of urine was collected for urinary concentration of amikacin.
I. Age, sex, and over-all general physical condition of patients treated with amikacin
TABLE
Age Range
17 - a5
24 - 81
;:
2:
22 3
21 4
1: I?]
l2 I:{
Average Median Sex
Male Female
White Black
Toxicity studies
Urologic Condition
Toxicity studies included complete blood count, SMA 12/60, and serum creatinines which were performed prior to, during (forty-eight to seventy-two hours), and at the end of therapy. Audiograms were carried out initially and at the completion of therapy to detect ototoxicity.
Prostatic Obstruction A. Carcinoma B. Hyperplasia
Results Table I describes age, sex, and over-all general physical condition of the patients. Prior to initiating therapy, all patients had a complete urologic evaluation, including cystoscopic examination. The majority of patients in both groups had similar underlying urologic conditions and underwent major urologic surgery. Amikacin was administered for an average of 7.7 and 8 days in the high- and low-dose groups, respectively (Table II). Average daily dose was 925 mg. in Group I and 490 mg. in Group II. Bacteriologic The most common isolates in Group I were Pseudomonas and Escherichia coli (Table III) and in Group II, E. coli and Proteus mirabilis were predominant (Table IV). At the completion of therapy, 23 of 25 isolates had been eradicated in Group I, while 25 of 25 isolates were eradicated at the end of therapy in Group II. Relapse rates were higher in Group I while superinfection rates were higher in Group II. Similar rates of reinfection were observed in both groups. Urinary concentrations of amikacin in the low-dose group ranged from 32 to 1,452 pg./ml. with a mean of 438 pg./ml. In the high-dose group, urinary concentrations ranged from 28 to 1,350 pg./ml. with a mean of 597 pg./ml. *Courtesy
UROLOGY
of Bristol
Laboratories,
/ AUGUST1977
Syracuse,
I VOLUMEX,
New York.
NUMBER2
Calculi A. Renal B. Ureteral Neurogenic Bladder
1
2
Reflux (bilateral)
3 (1)
1
Bladder - Carcinoma
1 (1)
0
( ) = major urological surgery.
TABLE
II. Presents dosage schedule of amikacin Group I WigW
Planned Dose Average Daily Dosage
Total Average Range Days Treated (Average) Median Range
15 q/kg/24 hrs
Group II (Lar) 7.5 mg/kg/24 hrs
926 mg
490 mg
6.2 gm 3-14.3 gm
3.7 gm 1.4 - 8.1 gm
7.7 days 7 days 5 - 14 days
8.0 days 8.0 days 5 - 13 days
Toxicity One patient with renal insufficiency treated with high-dosage amikacin had further evaluation of blood urea nitrogen and creatinine at the conclusion of treatment. This patient was treated for a total of seven days. Laboratory values returned to pretreatment levels one week post-therapy (Table V). Serial audiograms revealed no evidence of ototoxicity in either dosage group. One patient in the low-dosage group noted severe roaring in his ears (tinnitis) and amikacin was discontinued immediately. The tinnitis cleared within twenty-four hours (Table V).
111
TABLE ORGANISM
III.
Bacteriologic results of laboratory studies in Group Z
PRJZ-THERAPY Wange)
POST-THERAPY R dicated Pereistent MIC SuperinfectionReinfectionRelapse (iid of Rx) Infection Range
E. Coli
7
1.0-8.0
7
0
Pseudomonas
a
0.5-16
6
2
Proteus Rettgeri
3
1.0-8.0
3
0
Proteus mirabilis and Klebsiella
2
2
0
Proteus Mirabilie
1
8.0
1
0
Klebeiella
1
1.0
1
0
Enterobacter
1
4.0
1
0
Pseudomonasand 6 anitratum
1
:::
1
0
E. coli and Klebsiella
1
::;
1
0
TOTALS
5 1 1
it::
25
TABLE ORGANISM
32-64
23 (92%)
IV.
1
1 1
6
3
1
2
Bacteriologic results of laboratory studies in Group ZZ
POST-THERAPY PR@rRERAPY Eradicated Persistent Superinfection Reinfection Relapse 0. ta. (Range) (End of Rx) Infection
E. co11
7
1.0 - 4.0
7
0
1
0
0
Proteus mirabilis
5
1.0 - 4.0
5
0
1
0
0
Klebsiella
4
0.5 - 2.0
4
0
1
0
0
Pseudomonas
4
1.0 - 16
4
0
0
1
1
Proteus Rettgeri
1
1.0
1
0
0
0
0‘
Enterobacter
1
2.0
1
0
0
1
0
E. coli and Proteus mirabilie
:::
1
0
0
0
0
'
E. coli and Pseudomonas
1
0
0
0
0
1
1:::
Proteus morgani and 1 Pseudomonas
1
0
0
0
1
;:: 0
3
2
2
TOTALS
112
25
25 (100%)
UROLOGY
/ AUGUST1977
/ VOLUMEX,
NUMBER2
TABLE
V.
Surveillance of toxicity during amikacin theravu NO. of Patients
RENAL status
Test Blood Urea Nitrogen:
Group I (High)
Group II (Low)
1*
0
Increased No change or decreased
Creatinine:
24 1*
Increased No change or decreased
*Return&d to p+e-therapy
level
OTDLOGIC
Cochlea+
:
Decrease in hearing No change
Vestibular:
0 25
one week poet-therapy.
No. of Patients Group II (Low) Group I (High)
status
Test
24
25
Tinnitus No change
0
0
25
25
0
1
25
24
Comment This study was designed to determine the clinical effectiveness of low-dosage amikacin (7.5 mg./Kg./twenty-four hours) as compared with the recommended high-dosage (15 mg./ Kg./twenty-four hours) regimen in the treatment of complicated urinary tract infections. Results have indicated that both dosage schedules are comparable. As expected, in patients with structural changes of the urinary tract, failure rates on follow-up were high.5J Thirteen of 25 patients in the high-dosage group and 17 of 25 in those patients receiving the lowdosage regimen were considered cured at the end of the study. Renal toxicity was not a serious problem in either group with only 1 patient (Group I) showing an increase in serum blood urea nitrogen and creatinine at completion of therapy. This patient had laboratory evidence of renal insufficiency prior to initiation of therapy; and possibly if a lower dose of amikacin had been used, renal function would not have been altered. Previous reports8j11 concerning ototoxicity associated with amikacin have been correlated with the duration of therapy (usually greater than fourteen days), previous aminoglycoside therapy, and/or renal insufficiency. In this study cochlear ototoxicity was not observed. It is
UROLOGY
/ AUGUST 1977
/ VOLUME
X, NUMBER
2
interesting to note that the majority of our patients had received previously documented aminoglycoside therapy, and 16 per cent of the patients (5 in the high dose and 3 in the low dose) had evidence of renal insufficiency. It may be that prolonged therapy is more instrumental in causing evidence of ototoxicity since the mean average of therapy with amikacin in our study was eight days. We are unable to comment on the possible association of ototoxicity and diuretics, such as ethacrynic acid or furosemide, since none of our patients in this study received a diuretic. In conclusion, our data indicate that lowdosage amikacin is satisfactory in the treatment of complicated urinary tract infections, because of the high urinary concentrations (low - mean 438 pg./ml.) which far exceeded the MIC of sensitive organisms. In regard to complications, no ototoxicity was observed, and evidence of renal toxicity was seen in only 1 patient with renal insufficiency. 300 South Hawthorne Road North Carolina 27103
Winston-Salem,
References of 1. Finland M: Changing patterns of susceptibility common bacterial pathogens to antimicrobial agents, Ann. Intern. Med. 76: 1009 (1972). 2. Bryan LE, Shahrabadi MS, and Van Den Elzen HM: Gentamicin resistance in Pseudomonas aeruginosa: R-factormediated resistance, Antimicrob. Agents Chemother. 6: 191 (1974). 3. Chadwick P: Resistance of Pseudomonas aeruginosa to gentamicin, Can. Med. Assoc. J. 109: 585 (1973). 4. Holmes RK, Minshew BH, Gould K, and Sanford JP: Resistance of Pseudomonas aeruginosa to gentamicin and related aminoglycoside antibiotics, Antimicrob. Agents Chemother. 6: 253 (1974). 5. Sharp PM, Saenz, CA, and Martin RR: Amikacin (BBK-8) treatment of multiple drug resistant Proteus infections, ibid. 5: 435 (1974). 6. Meyer RD, Lewis RP, Hunter J, and White M: Gentamitin resistant Pseudomonas aeruginosa and Serratia marcescens in a general hospital, Lancet 1: 580 (1976). 7. Tally FP, et al: Amikacin therapy for severe gramnegative sepsis, Ann. Intern. Med. 83: 484 (1975). 8. Meyer RD, Lewis MD, Carmalt ED, and Finegold SM: Amikacin therapy for serious gram-negative bacillary infections, ibid. 83: 790 (1975). 9. Stamey TA, et al: Serum versus urinary antimicrobial concentrations in cure of urinary tract infections, N. Engl. J. ,Med. 22: II59 (1974). 10. Bauer AW, Kirby WMM, Sherris JC, and Turck M: Antibiotic susceptibility testing by a standard single disc method, Am. J. Clin. Pathol. 45: 493 (1966). 11. Valdivieso M, Feld R, Rodriguez V, and Bodey G: Amikacin therapy of infections in neutropenic patients, Am. J. Med. Sci. 270: 453 (1975).
113
OF COMPLICATED
INFECTIONS
WITH AMIKACIN
Comparison LLOYD
URINARY TRACT
of Low and High Dosage
H. HARRISON,
M.D.
From the Department of Urology, Bowman Gray School of Medicine, Winston-Salem, North Carolina
ABSTRACT -A randomized prospective study was carried out comparing the recommended dose of amikacin sulfate (Amikin) (15 mg. Kg.) with a lower dose (7.5 mg. Kg.) in the treatment of complicated urinary tract infections. A total of 50 patients were entered in the study over a period of sixteen months. Bacteriologic results were comparable in both groups. Laboratory values remained normal with the exception of 1 patient in the high-dose group who had renal insufficiency. No evidence of ototoxicity was recorded. Our data indicate that low dosage amikacin sulfate is satisfactory in the treatment of complicated urinary tract infections.
Within the last few years increasing numbers of in vitro gentamicin-resistant bacterial isolates have been reported. r* Many of these organisms are sensitive to amikacin (Amikin),5-8 a new semisynthetic aminoglycoside. At the dosage level now recommended for amikacin, high serum and urine concentrations far exceed the MIC of sensitive isolates. If it is true as proposed by Stamey et a1.g that cure of urinary infection is dependent on urinary antimicrobial concentration and not serum levels, use of lower than recommended doses of amikacin may be as effective in the treatment of those patients with urinary tract infections. In addition, the wellrecognized potentiality for ototoxicity and nephrotoxicity may be considerably lessened. A protocol was designed to compare the recommended dosage of amikacin against a lower dosage in the treatment of patients with complicated urinary tract infections. The randomization of 50 patients into a study program over a total period of sixteen months was carried out, and the results are reported herein. Method Patients were entered into the protocol who met the following criteria as having a compli-
110
cated urinary tract infection: (1) Males with prostatic obstruction secondary either to benign or malignant disease; and (2) males/females having stones, indwelling catheters, anatomic and/or functional changes of the urinary tract. Patients who were likely to receive other antimicrobials concomitantly with amikacin were excluded from the study. Patients were divided into two groups of 25 each. Group I was given high dosage amikacin, 15 mg./Kg./twenty-four hours (intramuscularly divided dose every twelve hours). Group II was given low dosage amikacin, 7.5 mg./Kg./twentyfour hours (intramuscularly divided dose every twelve hours). Amikacin dosage (Groups I and II) was adjusted in patients with renal impairment. The dosage interval was calculated by multiplying the serum creatinine by 9. Bacteriologic studies Two midstream clean-catch voided or catheterized specimens growing greater than lo5 organisms per milliliter were obtained. Urine cultures were carried out at forty-eight to seventy-two hours during therapy, on completion of therapy, and one week and four to six weeks after end of therapy. If cultures were
UROLOGY
/
AUGUST
1977
I
VOLUME
X, NUMBER
2
positive at any time during the course of treatment, this was considered an end point, and the patient was placed on another more suitable antibiotic. All bacteriologic isolates were identified by the standard method and tested with single disk sensitivities. lo Isolates were uniformly sensitive to the IO+g. disk* of amikacin. Tube dilution studies for MIC (minimal inhibitory concentration) were performed on all isolates to confirm sensitivity. At midtherapy, after the first dose, a 0 to 6hour sample of urine was collected for urinary concentration of amikacin.
I. Age, sex, and over-all general physical condition of patients treated with amikacin
TABLE
Age Range
17 - a5
24 - 81
;:
2:
22 3
21 4
1: I?]
l2 I:{
Average Median Sex
Male Female
White Black
Toxicity studies
Urologic Condition
Toxicity studies included complete blood count, SMA 12/60, and serum creatinines which were performed prior to, during (forty-eight to seventy-two hours), and at the end of therapy. Audiograms were carried out initially and at the completion of therapy to detect ototoxicity.
Prostatic Obstruction A. Carcinoma B. Hyperplasia
Results Table I describes age, sex, and over-all general physical condition of the patients. Prior to initiating therapy, all patients had a complete urologic evaluation, including cystoscopic examination. The majority of patients in both groups had similar underlying urologic conditions and underwent major urologic surgery. Amikacin was administered for an average of 7.7 and 8 days in the high- and low-dose groups, respectively (Table II). Average daily dose was 925 mg. in Group I and 490 mg. in Group II. Bacteriologic The most common isolates in Group I were Pseudomonas and Escherichia coli (Table III) and in Group II, E. coli and Proteus mirabilis were predominant (Table IV). At the completion of therapy, 23 of 25 isolates had been eradicated in Group I, while 25 of 25 isolates were eradicated at the end of therapy in Group II. Relapse rates were higher in Group I while superinfection rates were higher in Group II. Similar rates of reinfection were observed in both groups. Urinary concentrations of amikacin in the low-dose group ranged from 32 to 1,452 pg./ml. with a mean of 438 pg./ml. In the high-dose group, urinary concentrations ranged from 28 to 1,350 pg./ml. with a mean of 597 pg./ml. *Courtesy
UROLOGY
of Bristol
Laboratories,
/ AUGUST1977
Syracuse,
I VOLUMEX,
New York.
NUMBER2
Calculi A. Renal B. Ureteral Neurogenic Bladder
1
2
Reflux (bilateral)
3 (1)
1
Bladder - Carcinoma
1 (1)
0
( ) = major urological surgery.
TABLE
II. Presents dosage schedule of amikacin Group I WigW
Planned Dose Average Daily Dosage
Total Average Range Days Treated (Average) Median Range
15 q/kg/24 hrs
Group II (Lar) 7.5 mg/kg/24 hrs
926 mg
490 mg
6.2 gm 3-14.3 gm
3.7 gm 1.4 - 8.1 gm
7.7 days 7 days 5 - 14 days
8.0 days 8.0 days 5 - 13 days
Toxicity One patient with renal insufficiency treated with high-dosage amikacin had further evaluation of blood urea nitrogen and creatinine at the conclusion of treatment. This patient was treated for a total of seven days. Laboratory values returned to pretreatment levels one week post-therapy (Table V). Serial audiograms revealed no evidence of ototoxicity in either dosage group. One patient in the low-dosage group noted severe roaring in his ears (tinnitis) and amikacin was discontinued immediately. The tinnitis cleared within twenty-four hours (Table V).
111
TABLE ORGANISM
III.
Bacteriologic results of laboratory studies in Group Z
PRJZ-THERAPY Wange)
POST-THERAPY R dicated Pereistent MIC SuperinfectionReinfectionRelapse (iid of Rx) Infection Range
E. Coli
7
1.0-8.0
7
0
Pseudomonas
a
0.5-16
6
2
Proteus Rettgeri
3
1.0-8.0
3
0
Proteus mirabilis and Klebsiella
2
2
0
Proteus Mirabilie
1
8.0
1
0
Klebeiella
1
1.0
1
0
Enterobacter
1
4.0
1
0
Pseudomonasand 6 anitratum
1
:::
1
0
E. coli and Klebsiella
1
::;
1
0
TOTALS
5 1 1
it::
25
TABLE ORGANISM
32-64
23 (92%)
IV.
1
1 1
6
3
1
2
Bacteriologic results of laboratory studies in Group ZZ
POST-THERAPY PR@rRERAPY Eradicated Persistent Superinfection Reinfection Relapse 0. ta. (Range) (End of Rx) Infection
E. co11
7
1.0 - 4.0
7
0
1
0
0
Proteus mirabilis
5
1.0 - 4.0
5
0
1
0
0
Klebsiella
4
0.5 - 2.0
4
0
1
0
0
Pseudomonas
4
1.0 - 16
4
0
0
1
1
Proteus Rettgeri
1
1.0
1
0
0
0
0‘
Enterobacter
1
2.0
1
0
0
1
0
E. coli and Proteus mirabilie
:::
1
0
0
0
0
'
E. coli and Pseudomonas
1
0
0
0
0
1
1:::
Proteus morgani and 1 Pseudomonas
1
0
0
0
1
;:: 0
3
2
2
TOTALS
112
25
25 (100%)
UROLOGY
/ AUGUST1977
/ VOLUMEX,
NUMBER2
TABLE
V.
Surveillance of toxicity during amikacin theravu NO. of Patients
RENAL status
Test Blood Urea Nitrogen:
Group I (High)
Group II (Low)
1*
0
Increased No change or decreased
Creatinine:
24 1*
Increased No change or decreased
*Return&d to p+e-therapy
level
OTDLOGIC
Cochlea+
:
Decrease in hearing No change
Vestibular:
0 25
one week poet-therapy.
No. of Patients Group II (Low) Group I (High)
status
Test
24
25
Tinnitus No change
0
0
25
25
0
1
25
24
Comment This study was designed to determine the clinical effectiveness of low-dosage amikacin (7.5 mg./Kg./twenty-four hours) as compared with the recommended high-dosage (15 mg./ Kg./twenty-four hours) regimen in the treatment of complicated urinary tract infections. Results have indicated that both dosage schedules are comparable. As expected, in patients with structural changes of the urinary tract, failure rates on follow-up were high.5J Thirteen of 25 patients in the high-dosage group and 17 of 25 in those patients receiving the lowdosage regimen were considered cured at the end of the study. Renal toxicity was not a serious problem in either group with only 1 patient (Group I) showing an increase in serum blood urea nitrogen and creatinine at completion of therapy. This patient had laboratory evidence of renal insufficiency prior to initiation of therapy; and possibly if a lower dose of amikacin had been used, renal function would not have been altered. Previous reports8j11 concerning ototoxicity associated with amikacin have been correlated with the duration of therapy (usually greater than fourteen days), previous aminoglycoside therapy, and/or renal insufficiency. In this study cochlear ototoxicity was not observed. It is
UROLOGY
/ AUGUST 1977
/ VOLUME
X, NUMBER
2
interesting to note that the majority of our patients had received previously documented aminoglycoside therapy, and 16 per cent of the patients (5 in the high dose and 3 in the low dose) had evidence of renal insufficiency. It may be that prolonged therapy is more instrumental in causing evidence of ototoxicity since the mean average of therapy with amikacin in our study was eight days. We are unable to comment on the possible association of ototoxicity and diuretics, such as ethacrynic acid or furosemide, since none of our patients in this study received a diuretic. In conclusion, our data indicate that lowdosage amikacin is satisfactory in the treatment of complicated urinary tract infections, because of the high urinary concentrations (low - mean 438 pg./ml.) which far exceeded the MIC of sensitive organisms. In regard to complications, no ototoxicity was observed, and evidence of renal toxicity was seen in only 1 patient with renal insufficiency. 300 South Hawthorne Road North Carolina 27103
Winston-Salem,
References of 1. Finland M: Changing patterns of susceptibility common bacterial pathogens to antimicrobial agents, Ann. Intern. Med. 76: 1009 (1972). 2. Bryan LE, Shahrabadi MS, and Van Den Elzen HM: Gentamicin resistance in Pseudomonas aeruginosa: R-factormediated resistance, Antimicrob. Agents Chemother. 6: 191 (1974). 3. Chadwick P: Resistance of Pseudomonas aeruginosa to gentamicin, Can. Med. Assoc. J. 109: 585 (1973). 4. Holmes RK, Minshew BH, Gould K, and Sanford JP: Resistance of Pseudomonas aeruginosa to gentamicin and related aminoglycoside antibiotics, Antimicrob. Agents Chemother. 6: 253 (1974). 5. Sharp PM, Saenz, CA, and Martin RR: Amikacin (BBK-8) treatment of multiple drug resistant Proteus infections, ibid. 5: 435 (1974). 6. Meyer RD, Lewis RP, Hunter J, and White M: Gentamitin resistant Pseudomonas aeruginosa and Serratia marcescens in a general hospital, Lancet 1: 580 (1976). 7. Tally FP, et al: Amikacin therapy for severe gramnegative sepsis, Ann. Intern. Med. 83: 484 (1975). 8. Meyer RD, Lewis MD, Carmalt ED, and Finegold SM: Amikacin therapy for serious gram-negative bacillary infections, ibid. 83: 790 (1975). 9. Stamey TA, et al: Serum versus urinary antimicrobial concentrations in cure of urinary tract infections, N. Engl. J. ,Med. 22: II59 (1974). 10. Bauer AW, Kirby WMM, Sherris JC, and Turck M: Antibiotic susceptibility testing by a standard single disc method, Am. J. Clin. Pathol. 45: 493 (1966). 11. Valdivieso M, Feld R, Rodriguez V, and Bodey G: Amikacin therapy of infections in neutropenic patients, Am. J. Med. Sci. 270: 453 (1975).
113