THE JOURNAL OF INFECTIOUS DISEASES • VOL. 134, SUPPLEMENT © 1976 by the University of Chicago. All rights reserved.



AUGUST 1976

Single Daily Doses of Tobramycin in Therapy of Urinary Tract Infections From the Danville Urologic Clinic and the Department of Urology, Memorial Hospital, Danville, Virginia

Ralph R. Landes

The recently released aminoglycoside antibiotic tobramycin has been found effective in the treatment of infections caused by a broad spectrum of bacterial pathogens, especially gram-negative organisms including Pseudomonas and indolepositive Proteus [1]. The drug is not effective against most strains of enterococci, pneumococci, and streptococci [2]. Like gentamicin, it is ototoxic [3] and nephrotoxic [2] when administered in excessive dosage or at the usual dosage in patients with impaired renal function. The tY2 of the drug in the blood is approximately 2 hr in patients with normal rates of creatinine clearance and 57 hr in anephric patients [3]. It is almost completely excreted in the urine by glomerular filtration. Whereas the maintenance of optimal blood levels of tobramycin requires three or four divided im doses of 2-3.5 mg/kg per day, bactericidal levels usually exceeding the MIC of the pathogen by manyfold can be maintained in urine around the clock by a single im dose.

This work was supported in part by a grant from Eli Lilly and Company, Indianapolis, Indiana, and by the Memorial Hospital Urological Research Fund. Please address requests for reprints to Dr. Ralph R. Landes, Danville Urologic Clinic, 1040 Main Street, Danville, Virginia 24541.

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Increasingly convincing (but not conclusive) evidence has been gathered that the cure of urinary tract infections is related more to the urinary concentration of antibiotics than to their levels in serum. This concept has been established in regard to nitrofurantoin, naladixic acid, tetracycline [4], and, more recently, gentamicin [5]. In a single daily dose regimen for the treatment of urinary tract infections, one must choose carefully a dose that is large enough to maintain a high concentration in urine throughout the 24 hr but is not so large as to produce toxic peak serum levels. Mosegaard et al. [5], using single daily doses of gentamicin for urinary tract infections, demonstrated that such a dose could be chosen; a single daily im dose of 160 mg of gentamicin resulted in nontoxic serum levels, 24-hr bactericidal urine levels, and therapeutic results equal to those produced by a multiple dose regimen of 60-80 mg every 8 hr. The advantages of a regimen of a single daily dose are many. It allows many patients to receive treatment as outpatients, eliminates the discomfort of multiple daily injections, and reduces the amount of nursing care and expensive supplies. For these reasons this clinical trial of treatment of patients with urinary tract infections with a single daily im dose of tobramycin was undertaken.

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Results of therapy with tobramycin for infections caused by susceptible pathogens have been impressive. The usual multiple dose regimen is aimed at maintenance of the serum concentration of tobramycin above the minimal inhibitory concentration of the causative pathogen throughout the course of therapy. Evidence is accumulating, however, that the urinary concentration of antibiotics may be of ~reater importance than the serum concentration in the treatment of urinary tract infections. This concept has been supported by results of studies with nitrofurantoin, naladixic acid, tetracycline, and, more recently, gentamicin. The present study of 90 patients with urinary tract infections treated with a single intramuscular daily dose of tobramycin resulted in round-the-clock urinary levels of tobramycin that exceeded the minimal inhibitory concentration of the offending pathogen. The clinical and bacteriologic response to therapy was excellent, and no oto- or nephrotoxicity occurred. This regimen frequently allows for therapy on an outpatient basis, fewer painful injections for the patient, and the saving of nursing time and expensive supplies.

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Tobramycin for Urinary Tract Infections

Materials and Methods

Table t.

Susceptibility to tobramycin of 95 urinary isolates from 90 patients.

Organism Escherichia coli Pseudomonas Enterobacter Proteus rettgeri Proteus morganii Proteus mirabilis Enterococcus Providencia Paracolobactrum Staphylococcus Total

No. resistant! no. of isolates*

0/33 2/21

3/19 0/2

0/3 0/10 0/2 0/1 0/1 1/3 6/95

* Each of five patients had two isolates. Strains were considered to be resistant if the MIC was >8 ug/rnl and/or if the zone of inhibition to a 10-~g disk of tobramycin was < 16 mm in diameter.

Results

The distribution of the various urinary pathogens and their susceptibility to tobramycin in 608 successive positive cultures obtained from outpatients and in 238 cultures from hospitalized patients are presented in table 2. Except for enterococci and streptococci, the proportion of urinary isolates susceptible to tobramycin in vitro was striking. The regimen of a single daily dose of tobramycin was used in 90 patients, 40 of whom were outpatients. Levels in serum 2 hr after injection were below toxic levels; the means were 7.8 ug/rnl (range, 5.9-12.2 ug/rnl) on the first day of treat-

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Ninety adult patients of either sex whose underlying urological diseases represented a cross-section of conditions seen in urological practice were treated for their urinary tract infections with a single daily im dose of tobramycin for five to 15 days. Patients weighing ~64 kg received 160 mg, and the remainder received 200 mg daily. AU patients had serum creatinine levels of ~ 1.5 mg/l00 ml and blood urea nitrogen levels of ~25 mg/ 100 ml before treatment. None had gross evidence of auditory or vestibular dysfunction, nor had any patient received neurotoxic drugs in the recent past. All patients had significant bacteriuria (table 1) and clinical findings localizing the site of their urinary infections, except for five patients whose clinical status was designated as "urinary tract infection, site undetermined." Identification of the pathogens was made by standard bacteriologic methods. Urine cultures and colony counts were performed before, during, and at the end of treatment and at follow-up study one to four weeks later. Susceptibility of the pathogens to tobramycin was determined by the microtiter broth dilution method [6] for hospitalized patients and by the Food and Drug Administration (FDA) standardized disk diffusion technique [7] for outpatients. Of the the 95 isolates tested before treatment, 89 were susceptible to tobramycin (MIC of ~8 ug/rnl or zones of inhibition to the 1O-~lg disk of ~ 16 mm). Six isolates were marginally

resistant; patients with resistant pathogens other than these six were excluded from the study. Audiograms were performed before and after treatment in most patients. Automated 18-channel serum chemical determinations and complete blood counts were done before and at the end of treatment. Bioassays for concentrations of tobramycin in serum and urine were performed 2 hr after the first and last daily injection and at other intervals. The results of therapy were graded as follows. The clinical result was judged to be satisfactory if there was prompt clinical improvement (fever, pain, dysuria, frequency of urination). The pathogen was considered to be eliminated if urine samples contained 5,000 colonies /ml during treatment and at follow-up study. If, after an abacteriuric interval during and at the end of treatment, the same genus, still susceptible to tobramycin, was present at follow-up study in a concentration of >5,000 colonies/ml, then the case was judged to be a recurrence of the same genus (susceptible). Likewise, if the resistant genus present at follow-up study was the same one present during treatment, the case was considered to be a recurrence of the same genus (resistant). A case was considered to be a recurrence with a new pathogen if, after an abacteriuric interval during and at the end of therapy, a new genus was present in a count of >5,000 organisms/ml.

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Landes

Table 2. Incidence of various bacterial isolates susceptible to tobramycin in urine samples of 90 outpatients and hospitalized patients. Hospitalized patients

(%)

(% )

No. susceptible/no. of isolates (%) t

Escherichia coli Pseudomonas Klebsiella-Enterobacter Enterococcus Proteus mirabilis morganii rettgeri vulgaris Serratia Citrobacter Staphylococcus Streptococcus Providencia Edwardsiella Total

24 9

57/58(98) 19/21(90)

40 10

240/241 (99.7) 54/61 (89)

21 15

47/51(92) 11/36(31)

16 6

90/95(95) 4/35(11)

6 8 3

10 3 2 3

59/59(100) 19/19(100) 10/11 (91) 15/15(100)

7

13/14(93 ) 20/20 ( 100) 6/6(100 ) 5/5( 100) 1/6(17) 4/4(100) 14/17(82)

100

197/238(83)

* Isolates

3 2

were considered to be susceptible if the MIC was

~8

0.3 10 1 0.3 0.2 100

2/2 51/60(85) 0/7 2/2 1/1 547/608(90)

ug/rnl.

t Isolates were considered to be susceptible if the zone of inhibition of a 10-J.lg disk of tobramycin was

~ 16

mm in

diameter.

ment and 9.2 ug/rnl (range, 6.1-13.7 ug/rnl) on the last day (days 5-10). Mean concentrations in urine measured at the same time were 764 ug/rnl (range, 170-1,908 ug /rnl ) and 714 ug/rnl (range, 150-3,535 ug/rnl ), respectively. The concentration of tobramycin in urine far exceeded the MIC of the causative pathogen throughout the 24 hr between injections, usually by manyfold (table 3). The concentration in serum, although still measurable, fell to less than the MIC of many pathogens 24 hr after injection. Table 3. Concentrations of tobramycin in serum and urine at various times after the im injection of a single daily dose in 90 patients with urinary tract infections. Concentration of tobramycin in ug / ml (range) Hr after injection 4 7-8 12-14 15 19 21-22 24

No. of samples

Serum

1 2 15 1 8 7 3

2.9 5 0.32 0.28 0.32 0.62 0.62

The clinical response to therapy was usually prompt and impressive (table 4), as was the bacteriologic response (table 5). The few unsatisfactory clinical responses were in patients with the most complicated underlying urological abnormalities: renal calculi, obstructive uropathy, carcinoma, and paraplegia. These patients accounted for almost all of the bacteriologic failures. There was no significant elevation in the level of serum creatinine and/or blood urea nitrogen in any patient. In no instance was there a significant change in the audiograms or any clinical indication of vestibular dysfunction. The single daily dose regimen for tobramycin in the therapy of urinary tract infections was safe and effective and is recommended for appropriate clinical use.

Urine 63 63 96 31 57

216 (59-68) (10-688) 212 (45-348) (9-58) (14-83)

References 1. Landes, R. R., Melnick, I., Hoffman, A., Fehrenbaker, L. Tobramycin, a new aminoglycoside antibiotic: experience in urinary tract infections. South. Med. J. 68:116-117, 1975. 2. Preston, D. A., Wick, W. E. Preclinical assessment of the antibacterial activity of nebrarnycin factor

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Incidence

Incidence Organism

Outpatients

No. susceptible/no. of isolates (% ) *

Tobramycin for Urinary Tract infections

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Table 4. Results, according to diagnosis, of treatment of patients with urinary tract infections caused by various bacterial pathogens with a single daily dose of tobramycin. Bacteriologic results

Diagnosis (no. of cases)

Total (90)

No. of failures to eliminate pathogen

No. of cases of pathogen eliminated

(% )

(% )

57 (92) 14 (93) 3 (60) 1 5 (83)

6

80 (89)

8 (9)

1

No. of recurrences (% ) Same genus Susceptible

Resistant

New genus

46 (74) 13 (87) 3 (60) 1

2

3

5 2 1

68 (76)

3 (3)

3 (3)

8 (9)

1

Table 5. Results, according to organism, of treatment of patients with urinary tract infections caused by various bacterial pathogens with a single daily dose of tobramycin. No. of recurrences Type of infection, organism (no. of cases) Single-organism infections Escherichia coli (28) Pseudomonas (21) Enterobacter (18) Proteus rettgeri (1) morganii (3) mirabilis (8) Enterococcus (1) Providencia (I) Paracolobactrum (1) Staphylococcus (3) Mixed infections E. coli + P. rettgeri (1) E. coli + P. mirabilis (2) E. coli + Enterobacter (1) E. coli + enterococcus (1) Total (90)

No. of cases of pathogen eliminated (% )

No. of failures to eliminate pathogen

Susceptible

Resistant

23 (82) 15 (71) 11 (61)

2 1 4

0 2 0

2

1

0 1

3 2

1 2 7 (88) 0 1 0 3

0 1 0 0 0 0 0

0 0 0 1 0 0 0

0 0 0 0 0 0 0

0 0 1 0 0 1 0

1 2 1 1

0 0 0 0

0 0 0 0

0 0 0 0

0 0 0 0

68

8

3

3

8

6. Antimicrob. Agents Chemother. 1970: 322-327, 1971. 3. Brummett, R. E., Meikle, M. M., Vernon, 1. A. Ototoxicity of tobramycin in guinea pigs. Arch. Otolaryngol. 94:59-63, 1971. 4. Stamey, T. A., Fair, W. R., Timothy, M. M., Millar, M. A., Mihara, G., Lowery, W. Serum versus urinary antimicrobial concentrations in cure of urinary-tract infections. N. Engl. J. Med. 291: 1159-1163, 1974. 5. Mosegaard, A., Smith, D. I., Madsen, P. O. Single

Same genus New genus

daily dosage treatment of urinary tract infections with gentamicin. In Proceedings of the Eighth International Congress of Chemotherapy, Athens, September 8-14, 1973. Vol. 2. Hellenic Society of Chemotherapy, Athens, 1974, p. 476-481. 6. Manual for microtube dilution antibiotic susceptibility testing. Canaleo Co. (Ames Co.) 1972. Elkhart, Ind. 46514. 7. Food and Drug Administration. Standardized disc susceptibility test. Federal Register, 1972 37: 20527-2052~ 1972.

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Pyelonephritis (62) Cystitis (15) Urinary infection (5) Epididymitis (2) Prostatitis (6)

No. of cases with satisf actory clinical results (% )

Single daily doses of tobramycin in therapy of urinary tract infections.

THE JOURNAL OF INFECTIOUS DISEASES • VOL. 134, SUPPLEMENT © 1976 by the University of Chicago. All rights reserved. • AUGUST 1976 Single Daily Dose...
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