THE JOURNAL OF INFECTIOUS DISEASES

• VOL. 134, SUPPLEMENT

© 1976 by the University of Chicago. All rights reserved.



AUGUST 1976

Emergence of Gentamicin-Resistant Bacteria: Experience with Tobramycin Therapy of Infections Due to Gentamicin-Resistant Organisms

A computerized system for testing and surveillance of bacterial susceptibility to antibiotics was used in monitoring the emergence of gentamicin-resistant strains of aerobic and facultative gram-negative bacilli at Massachusetts General Hospital since the release of gentamicin for clinical use in 1971. During the period studied, there was a significant increase in the prevalence of gentamicin-resistant bacteria, particularly among Pseudomonas, Acinetobacter (Herellea) , and Proteus and, more recently, among Enterobacter and Klebsiella. Most gentamicin-resistant strains of Pseudomonas aeruginosa and Acinetobacter calcoaceticus var. anitratum (Herellea vaginicola i retained susceptibility to tobramycin. Of the other gentamicin-resistant organisms, most were also resistant to tobramycin. Twelve patients with infections caused by gentamicin-resistant organisms were treated with tobramycin. AlI 12 patients were seriously iII, and all but one had failed to respond to previous therapy with gentamicin. Nine patients responded favorably to tobramycin, and six were cured. P. aeruginosa and A. calcoaceticus var. anitratum were most frequently the infecting organisms in these patients. Patients received tobramycin for three to 42 days; no significant drug-related toxicity was noted. These results emphasize the increasing clinical importance of gentamicin-resistant bacteria and suggest that tobramycin may be effective for treatment of some, but not all, infections caused by gentamicin-resistant bacteria.

resistant bacteria during a four-year period (19711974) and have been able to ascertain the susceptibility of the majority of these isolates to tobramycin. In this time span we have determined the susceptibility of > 60,000 isolates of bacteria to gentamicin and have determined susceptibility of > 50,000 isolates to both gentamicin and tobramycin. These figures represent unique isolates and do not include replicates of isolates of the same species from a given patient [1]. These data serve as the basis for this report. Also induded are the results of our clinical experience with the use of tobramycin for the treatment of infections due to gentamicin-resistant organisms.

Gentamicin was released for clinical use at Massachusetts General Hospital in early 1971. Since that time, we have used a computerized system [1] to monitor the gentamicin susceptibility of all aerobic and facultative gram-negative bacteria submitted to the clinical bacteriology laboratory for routine susceptibility testing. Susceptibility to tobramycin likewise has been determined for clinical isolates since early 1972. Thus we have been able to follow the emergence of gentamicin-

The authors acknowledge the valuable assistance provided by James Poitras, Carl Lazarus, Bette Mercier, and Marion Cameron of the Laboratory of Computer Science, Massachusetts General Hospital. The clinical studies were supported by Eli Lilly and Company. Please address requests for reprints to Dr. Robert C. Moellering, Jr., Infectious Disease Unit, Massachusetts General Hospital, Boston, Massachusetts 02114.

Materials and Methods

Susceptibility testing. Routine tests for susceptibility to antimicrobial agents were performed

S40

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From the Infectious Disease Unit, Department of Medicine and the Francis Blake Bacteriology Laboratories, Massachusetts General Hospital,' and the Departments of Medicine and of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts

Robert C. Moellering, Jr., Christine Wennersten, and Lawrence J. Kunz

Gentamicin Resistance and Tobramycin Therapy

Results

Epidemiological observations. Between July 1, 1971 and December 31, 1974, susceptibility to gentamicin was determined for >60,000 unique isolates (excluding replicates from the same patient) of aerobic and facultative gram-negative bacilli, and susceptibility to both gentamicin and tobramycin was determined for > 50,000 unique isolates. Table 1 gives the results of testing by six-month intervals for the three and one-half years of the study. In 1971, only among Alcaligenes species, A cinetobacter calcoaceticus var. lwoffi (Mima polymorpha) ~I Providencia species, and Pseudomonas maltophilia were as many as 15 % of the strains resistant to gentamicin. Thus at the time of initiation of routine clinical use of gentamicin at Massachusetts General Hospital, there was little background of gentamicin resistance among aerobic and facultative gram-negative bacilli. Similar observations were made for tobramycin (beginning in early 1972), and, as was the case with gentamicin, significant resistance to tobramycin was seen only among Alcaligenes, A. calcoaceticus var. lwoffi, Providencia, and P. maltophilia. By 1974, however, increasing numbers of A lcaligenes and A. calcoaceticus var. lwoffi as well as Acinetobactercalcoaceticus var. anitratum (Herellea vaginicola), Proteus rettgeri, P. maltophilia, and other Pseudomonas species, including P. aeruginosa, were resistant to gentamicin. In general, the findings for tobramycin paralleled those for gentamicin, except among Pseudomonas species, P. aeruginosa, and A. calcoaceticus var. anitratum, against which tobramycin remained considerably more effective than gentamicin. The magnitude of the increase in prevalence of gentamicin-resistant isolates between July 1971 and December 1974 is shown in figure 1. A steady upward trend in the number of gentamicin-resistant isolates is evident. As is also shown in figure 1, the prevalence of tobramycin-resistant organisms rose steadily during the period of the study, despite the fact that the use of this drug was limited to experimental trials in less than 40 patients. The gentamicin-resistant organisms are more precisely identified in table 2, which shows the total number of gentamicin-resistant strains of

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according to the single disk method of Bauer et a1. [2], except that a mechanical method was used for inoculation of plates for susceptibility tests [3], and a computer-associated electronic zone analyzer was used for measurement, recording, and interpretation of zones of inhibition [1]. For both gentamicin and tobramycin, zone diameters were interpreted as follows: ~ 11 mm == resistant; 12-13 mm == intermediate; ;;? 14 mm == susceptible. All data were stored in the computer for subsequent analysis. In addition, an alerting system on the computer terminal enabled the technician reading the susceptibility results to identify and retain all of the gentamicin-resistant strains for further detailed testing. A subsample of isolates, including all of those from the patients reported herein, was also tested for susceptibility to gentamicin and tobramycin with the broth-dilution method [4]; dextrose phosphate broth (Pfizer, New York, N.Y.), which had a calcium content of 31 mg/liter and a magnesium content of 17 mg/Iiter, and Mueller-Hinton broth supplemented . with calcium (49-56 mg/ liter) and magnesium (24 mg/liter) were used. Organisms for which the MIC of gentamicin or tobramycin was ;;? 8 I-lg/ml were considered resistant. Clinical studies. The patients treated with tobramycin were studied prospectively by one of the authors (R.C.M.). Many of the terms used to define the response to therapy are self-explanatory. However, in certain instances, further definition is necessary to prevent ambiguity. The terms that may require such definition are as follows. Clinical response. Excellent: complete resolution of symptoms and of objective evidence of disease during therapy. Improved: improvement in symptoms and in objective evidence of disease without complete resolution during therapy. Unsatisfactory: minimal or no improvement during therapy. Bacteriological response. Excellent: eradication of infecting organism (s) from site of infection. Failure to eliminate organism: persistence of infecting organism in cultures from site of infection. Outcome. Cure: excellent clinical and bacteriological responses without evidence of recurrent infection four weeks after discontinuation of therapy.

841

1172-6172

318 71 95 1,415 99 99 39 92 84 91 93 92 933 99 99

318 90 ... 1,419 99 ... 44 81 ... 138 88 ... 871 99 ...

"

91 697 45 73 131

88 99 66 80 100

... ... ... . ...

122 816 57 96 203

} 310

279 98 . .. 95 97 60 83 100

100 99 71 86 98

93 93

11 100 100

...

18 100

55 45 98 99 99 99 99 98

. ... ... .,

52t 100 99 100

20 255 3,069 610

No. Gm Tm

* Number of unique isolates [1]. t Percentage of isolates susceptible to the indicated antibiotic.

}

44 241 2,783 640

Alcaligenes species Citrobacter species Escherichia coli Enterobacter species Enterobacter hainiae (Hainia alvei) Acinetobacter calcoaceticus var. anitratum Klebsiella species A. calcoaceticus var. lwoffi Proteus species Proteus mirabilis Proteus morganii Proteus rettgeri Proteus vulgaris Pseudomonas species Pseudomonas aeruginosa Pseudomonas maltophilia Providencia species Serratia species

...

No.* Gm Tm

Organism

7171-12171

}

66 99 99 99 92

63 98 98 99

115 975 51 78 202

90 97 48 88 99

396 92 91 98 50 88 95

91 }

37 78 77 46 91 88 978 99 99

398 76 96 1,506 99 99

14 92

42 316 3,200 748

No. Gm Tm

7172-12172

44 97 99 99 45 99 99 99

93 814 57 58 126

88 96 49 74 100

277 96

89 99 52 70 95

94

29 96 83 43 95 95 868 99 99

413 78 96 1,291 99 99

10 100 100

34 180 3,231 587

No. Gm Tm

1173-6173

58 45 96 98 99 99 99 99

32 25 819 207 67 68 66 1,002 61 76 139

93 100 99 100 92 98 80 95 72 84 100

90 100 99 99 92 98 84 98 75 82 95

521 58 87 1,403 99 99

13 100 100

24 157 3,245 650

No. Gm Tm

7173-12173

20 9 856 199 89 36 60 791 73 51 138

70 88 99 99 70 100 86 88 45 76 99

75 88 98 98 71 97 98 98 47 82 97

15 33 826 190 75 52 90 1,063 103 44 165

86 93 99 98 65 74 83 95 30 68 99

86 100 99 98 72 94 86 99 36 86 93

420 90 97 1,402 97 97

53 56 98 98 99 99 93 93

458 54 87 1,376 98 97

26 159 3,281 645

9 100 100

29 41 98 98 99 99 99 98 21 100 100

17 194 3,271 566

7174-12174

No. Gm Tm

1174-6174

No. Gm Tm

Table 1. Susceptibility to gentamicin (Gm) and tobramycin (Tm) of gram-negative bacilli isolated at Massachusetts General Hospital (Boston, Mass.), 1971-1974.

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Gentamicin Resistance and Tobramycin Therapy

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~ GENTA-R,TOBRA-R

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GENTA-R, TOBRA-NT

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1971 each species isolated between July 1971 and December 1974. Also given are the susceptibilities to tobramycin for these strains. A. calcoaceticus var. anitratum made up the largest number of isolates, followed by P. aeruginosa, P. maltophilia, P. rettgeri, Flavobacterium species, Providencia species, Klebsiella species, Enterobacter species, and Alcaligenes species. Except for A. calcoaceticus var. anitratum and P. aeruginosa, most of the gentamicin-resistant strains were also resistant to tobramycin. Clinical experience with tobramycin for therapy of infections due to gentamicin-resistant organisms. During the period encompassed by this study, a significant number of infections were caused by gentamicin-resistant organisms. Tobramycin was used to treat 12 patients infected with organisms that were resistant to gentamicin as determined by single-disk susceptibility testing. Although disk susceptibility testing served as the screening procedure for initial inclusion of patients in this study, gentamicin resistance was further confirmed by broth dilution tests (table 3) . Because of the known effect of divalent cations on bacterial susceptibility to aminogly-

Jut-Dec Jan-Jun Jot-Dec Jan-Jun Jul-Dec

L.-1972---J L.-1973 --J '--1974--J

cosidic aminocyclitols and other antibiotics, all organisms were tested both in dextrose phosphate broth and Mueller-Hinton broth with added calcium and magnesium. MICs of gentamicin and tobramycin for P. aeruginosa increased when tested in Mueller-Hinton broth supplemented with calcium and magnesium, and in several instances organisms that appeared to be susceptible to gentamicin when tested in a medium containing low to moderate amounts of divalent cations were resistant when tested in a medium with more nearly physiological concentrations of calcium and magnesium. Clinical results are summarized in tables 4-6. In general, the infections occurred among critically ill patients; all were hospital-acquired. In all but one instance, the infections represented failures to respond to the gentamicin therapy that preceded treatment with tobramycin. Clinical improvement was noted in nine of the 12 patients, and six were cured, although two subsequently died of other causes. Best results were obtained among five patients with urinary tract infections complicated by anatomic abnormalities (table 4). In spite of the complications, four of the five

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Figure 1. Frequency of isolation of gentamicin- and tobramycinresistant organisms at Massachusetts General Hospital from June 1971 through December 1974. GENTA = gentamicin; TOBRA = tobramycin; S = susceptible; R = resistant; NT = not tested.

544

Moellering, Wennersten, and Kunz

Table 2. Gentamicin-resistant organisms: summary of total isolates at Massachusetts General Hospital, July 1971 through December 1974.

Organism

Rank

13

14 15 16 17 18 19 20 21 22 23

Total

1,114

52

426 214 172 153 106 98 92 81 59 58 52 38 28 26 21 20

78 5 4 1 11 2 4 5

13

11 8

7 7 4 2,808

28

21 17

15 12 30 19 0 11 45 12 0 0

0 38

patients responded well to therapy, and three were cured. Both of the patients who were not cured showed favorable responses initially; however, a tobramycin-resistant strain emerged during therapy in one patient who had infected renal cysts; in the other patient, relapse with a similar, tobramycinsusceptible organism occurred shortly after therapy. The latter patient had a recurrent tumor in the bladder. As can be seen in table 5, the results of treatment for patients with pneumonia were not as good as for those with urinary tract infections. One patient (L.C.) had an excellent clinical response, with radiological clearing of pneumonia (although one of the infecting organisms persisted in his sputum), but he eventually died from unrelated causes. The other three patients did not have adequate clinical responses. However, each of the three was very near death when treatment with tobrarnycin was initiated; one died after

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2 3 4 5 6 7 8 9 10 11 12

Acinetobacter calcoaceticus var. anitratum Pseudomonas aeruginosa Pseudomonas maltophilia Proteus rettgeri Flavobacterium species Providencia species Klebsiella species Enterobacter species A lcaligenes species Pseudomonas species Pseudomonas cepacia Escherichia coli Proteus species A. calcoaceticus var. lwoffi Proteus mirabilis Citrobacter species Bordetella bronchiseptica Unidentified gram-negative bacilli Comamonas terrigeni Proteus vulgaris Proteus morganii Serratia species CDC groups II-IV

No. isolated

Percentage susceptible to tobramycin

three days and another after seven days of therapy. In the latter patient (A.B.), the infecting organisms subsequently proved resistant to tobramycin as well as to gentamicin. A mixed set of responses was noted among the other patients with infections treated in this study (table 6). A patient with an infected total hip replacement was not cured, but this fact was not surprising since she refused surgical intervention. Thus, the foreign body which precipitated her infection could not be eliminated. A young girl with osteomyelitis of the radius and ulna due to P. aeruginosa was cured after 42 days of treatment with tobramycin. Likewise, a burned patient with persistent septicemia due to A. calcoaceticus var. anitratum and P. aeruginosa was cured after 18 days of therapy with tobramycin, although he subsequently died from unrelated causes. The patients in this study received tobramycin for periods of three to 42 days. No significant toxicity was noted, despite the fact that all but one patient had had previous intensive treatment with aminoglycosidic aminocyclitols and one (F.A. ) had significant renal damage from previous aminoglycoside therapy when tobramycin administration was started. There was no clinical evidence of damage to the auditory or vestibular portions of the eighth nerve in any of the patients, although formal testing was done in only two patients. In four of eight patients in whom the rate of creatinine clearance was measured before and after therapy, the clearance rate decreased by ~ 33% during tobramycin treatment. In these four patients the concentration of serum creatinine also increased slightly, but in all four the values remained within the normal range. One of these patients received concomitant furosemide, which may have contributed to renal impairment. In one additional patient, levels of blood urea nitrogen and creatinine increased before death, but these changes were probably unrelated to treatment with tobramycin. Thus, there was evidence of impairment of renal function during tobramycin therapy in five of 12 patients. In three patients the impairment was probably related to tobramycin; in all three the degree of impairment was mild (detectable only by determination of creatinine clearance rate), and in none of these patients did serum creatinine values increase to levels above normal.

S S I

S S S S

P. aeruginosa

P. aeruginosa

A. calcoaceticus var. anitratum Pseudomonas maltophilia Enterobacter species

P. aeruginosa

A. calcoaceticus var. anitratum P. aeruginosa

P. aeruginosa

A. calcoaceticus var. anitratum (1) A. calcoaceticus var. anitratum (2)

L.K.

A.L.

P.M.

T.P.

W.R.

K.W.

R.Y.

=

S susceptible; I intermediate. t Diameter (mm) of zone of inhibition. t NT not tested.

=

S

P. aeruginosa

D.K.

=

S

Acinetobacter calcoaceticus var. anitratum P. aeruginosa

L.c.

* R = resistant;

S

P. aeruginosa

P.B.

S R

14

S

R

R S

20

16 23 18

13 R

R

25

17

R

R R I

R

17 17

14 14

R S

R

12 25

26

11

R

23 17 R R

Interpretation

1

11

6

8

15

31

4

1

0.5 11

8

11

19

6

0.5

8

12

6

31 16

1

2

0.25

0.25

6

6

7

9

18

7

31

8

1 250

9

4

1

6

16

2

8

8 4

4

31 16 2

4

2 4

NT 2

NTt

62

MHB

DPB

Tobramycin

l')

;::

>1,000 250 16 1 500 62 31 31

62

250 125

125 31 2 4 8

62

2

8

16 8

8

8

62 0.5

NT

NT

8

S' NT

250

0.5

3

31 31 8

~

VI

VJ

'


Q

Bacteriological

Clinical responset

Results of tobramycin therapy for miscellaneous infections due to gentamicin-resistant bacteria.

D.K.

Patient (age, sex)

Table 6.

NOTE. All patients had previously received gentamicin therapy. * R = resistant; S = sensitive; I = intermediate. t See Materials and Methods for definition of terms.

A. calcoaceticus var. anitratum (1) A. calcoaceticus var. anitratum (2)

A. calcoaceticus var. anitratum Pseudomonas maltophilia Enterobacter

Pneumonia

P.M. (16, F)

A cinetobacter calcoaceticus var. anitratum Pseudomonas aeruginosa

Organism

Pneumonia

Type of infection

Disk susceptibility to*

Results of tobramycin therapy for respiratory tract infections due to gentamicin-resistant bacteria.

t.c. (21, M)

Patient (age, sex)

Table 5.

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Moellering, Wennersten, and Kunt:

S48

organisms for which the MIC of tobramycin was ~ 8 ug/rnl. In this context, it is of interest to note the effect of the .concentration of divalent cations (magnesium, calcium) on the in vitro susceptibility of our strains of P. aeruginosa. As has been suggested in recent reports [16, 17], the MICs of tobramycin and gentamicin were two to eight times higher when tests were done in MuellerHinton broth supplemented with physiological concentrations of calcium and magnesium than when tests were done in dextrose phosphate broth, which contained lower concentrations of these divalent cations. Although not proven, it is likely that testing in the former medium is more valid since the concentrations of calcium and magnesium in this medium are similar to those that occur in vivo. The overall utility of tobramycin for the treatment of infections due to gentamicin-resistant organisms cannot be determined from this study. Our limited clinical experience, however, does suggest that tobramycin may be especially valuable in treating infections due to gentamicin-resistant strains of P. aeruginosa. The drug may also be useful for treatment of infections due to A. calcoaceticus var. anitratum, even though for some of the latter species that were resistant to gentamicin, the MICs of tobramycin were higher than would have been predicted by disk testing. Therefore, the overall utility of tobramycin treatment for infections due to A. calcoaceticus var. anitratum remains to be determined. We have not used tobramycin therapy for sufficient numbers of patients with infections caused by other species of gentamicin-resistant bacteria to generalize our results. However, our data from in vitro tests suggest that the majority of gentamicin-resistant bacteria (except the pseudomonads and A. calcoaceticus var. anitratum) may also be resistant to tobramycin. This observation is disturbing and emphasizes the need for careful testing of susceptibility of the causative organisms when dealing with infections due to gram-negative bacilli, especially in hospitalized patients. References

c., Jr., Mercier, B. A., Kunz, L. J., Poitras, J. W. Evaluation of a computer-associated electronic zone analyzer in single disc antimicrobial susceptibility testing. Antimicrob. Agents Chemother. 2:95-102, 1972.

1. Moellering, R.

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especially since the administration of tobramycin was restricted to investigational use in fewer than 40 patients during the period of this study. Thus it seems likely that the use of gentamicin may select out strains of bacteria that are also crossresistant to tobramycin, especially among organisms other than the pseudomonads. Concomitant with the isolation of increasing numbers of gentamicin-resistant organisms in the bacteriology laboratory, we have seen increasing numbers of infections due to gentamicin-resistant bacteria. To date, all of these infections have been hospital-acquired, and most, but not all, have occurred in severely debilitated patients. Thus, while it is clear that gentamicin-resistant bacteria can cause severe and even fatal infections in hospitalized patients, our data do not enable us to determine with certainty that these organisms are as virulent or invasive as their gentamicinsusceptible counterparts. Because many of the gentamicin-resistant bacteria are resistant to multiple antibiotics, therapy of infections caused by these organisms is often difficult, and new or even potentially toxic agents must sometimes be employed. We have used tobramycin to treat 12 patients with infections due to gentamicin-resistant organisms. All but one of these patients had received and failed to respond to gentamicin therapy, a result attesting to the clinical significance of the gentamicin resistance in these cases. In consideration of the fact that most of the patients were critically ill and had failed to respond to antibiotic therapy before tobramycin administration was started, our therapeutic results (75 % favorable response, 50% cure rate) seem quite promising. It is probable that the results would have been better had tobramycin been given earlier rather than been used as a "last resort," as was the practice in this series. The degree of improvement in outcome with this approach, however, is open to question since, in a number of our failures, the infecting organisms were also relatively resistant to tobramycin (although in almost all instances the MICs of tobramycin were lower than those of gentamicin). In general, the therapeutic results were roughly related to the susceptibility of the infecting organism to tobramycin. Indeed, three of the six patients who were not cured were infected with

Gentamicin Resistance and Tobramycin Therapy

12.

13.

14.

15.

16.

17.

of resistance of Providencia stuartii to multiple antibiotics: speciation and biochemical characterization of Providencia. J. Infect. Dis. 129: 353357, 1974. Kabins, S., Nathan, c., Cohen, S. Gentamicinadenylyltranferase activity as a cause of gentamicin resistance in clinical isolates of Pseudomonas aeruginosa, Antirnicrob. Agents Chemother. 5:565-570, 1974. Bryan, L. E., Shahrabadi, M. S., Van Den Elzen, H. M. Gentamicin resistance in Pseudomonas aeruginosa: R-factor-mediated resistance. Antimicrob. Agents Chemother. 6: 191-199, 1974. Holmes, R. K., Minshew, B. H., Gould, K., Sanford, J. P. Resistance of Pseudomonas aeruginosa to gentamicin and related aminoglycoside antibiotics. Antimicrob. Agents Chemother. 6: 253262, 1974. Noriega, E. R., Leibowitz, R. E., Richmond, AS., Rubinstein, E., Schaefler, S., Simberkoff, M. S., Rahal, J. J., Jr. Nosocomial infection caused by gentamicin-resistant, streptomycin-sensitive Klebsiella. J. Infect. Dis. 131(Supp1.):S45-S50, 1975. Reller, L. B., Schoenknecht, F. D., Kenny, M. A., Sherris, J. C. Antibiotic susceptibility testing of Pseudomonas aeruginosa: selection of a control strain and criteria for magnesium and calcium content in media. J. Infect. Dis. 130:454-463, 1974. D'Arnato, R. F., Thornsberry, c., Baker, C. N., Kirven, L. A. Effect of calcium and magnesium ions on the susceptibility of Pseudomonas species to tetracycline, gentamicin, polymyxin B, and carbenicillin. Antimicrob. Agents Chemother. 7:596-600, 1975.

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2. Bauer, W. W., Kirby, W. M. M., Sherris, J. c., Turck, M. Antibiotic susceptibility testing by a standardized single disc method. Am. J. Clin. Pathol. 45: 493-496, 1966. 3. Kunz, L. J., Moellering, R. C., Jr. Mechanical method of inoculating plates for antibiotic sensitivity testing. Appl. Microbiol. 22: 476-477, 1971. 4. Anderson, T. G. Testing of susceptibility to antimicrobial agents in body fluids. In J. E. Blair, E. H. Lennette, and J. P. Truant [ed.]. Manual of clinical microbiology. American Society for Microbiology, Bethesda, Md., 1970, p. 299-310. 5. Waitz, J. A., Weinstein, M. J. Recent microbiological studies with gentamicin. J. Infect. Dis. 119:355360, 1969. 6. Kirby, W. M. M., Standiford, H. C. Gentamicin: in vitro studies. J. Infect. Dis. 119:361-363, 1969. 7. Weinstein, M. J., Drube, C. G., Moss, E. L., Jr., Waitz, J. A. Microbiologic studies related to bacterial resistance to gentamicin, J. Infect. Dis. 124(Suppl.) :SI1-S17, 1971. 8. Shulman, J. A., Terry, P. M., Hough, C. E. Colonization with gentamicin-resistant Pseudomonas aeruginosa, pyocine type 5, in a burn unit. J. Infect. Dis. 124(Suppl.):SI8-S23, 1971. 9. Weinstein, M. J. The microbiology of gentamicin resistance. Acta PathoI. Microbiol. Scand. 81 (Suppl. 241) :99-106, 1973. 10. Washington, J. A, II, Senjem, D. H., Haldorson, A, Schutt, A. H., Martin, W. J. Nosocomially acquired bacteriuria due to Proteus rettgeri and Providencia stuartii. Am. J. Clin. PathoI. 60:836838, 1973. 11. Overturf, G. D., Wilkins, J., Ressler, R. Emergence

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Emergence of gentamicin-resistant bacteria: experience with tobramycin therapy of infections due to gentamicin-resistant organisms.

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