Comparative activity of tobramycin and gentamicin against Pseudomonas, Proteus and Providencia species Ian B.R. Duncan, md,
frcp[c],
frc
path; John L. Penner,
ph d
gram-negative bacilli resistant to pres¬ ently available antibiotics. Tobramycin reportedly has greater activity than gentamicin against Ps. aeruginosa1 and is effective against some strains re¬ sistant to gentamicin.3'9,10 Other inves¬ tigators have reported that gentamicinresistant Ps. aeruginosa strains were also resistant to tobramycin.11 There have also been conflicting reports on the relative activity of the two anti¬ biotics against other nosocomial gramnegative bacilli, such as indole-positive species of Proteus4'12 which are re¬ sistant to many antibacterial agents. The present investigation is an at¬ tempt to resolve some of these discrepancies by testing the comparative activities of the two antibiotics against large collections of Ps. aeruginosa, Pr. The new aminoglycoside antibiotic to¬ rettgeri, Pr. morganii, Pr. vulgaris and bramycin is the most active component1 Providencia stuartii. Strains of three of of nebramycin, a mixture of antimicro¬ these five species were typed to ensure bial substances2 produced by Strepto- that the collection consisted of a widely myces tenebrarius. Its broad antibac¬ representative variety of types. terial spectrum is similar to that of Resume: Activite compare"e de la gentamicin3"5 and it includes Pseudo¬ Materials and methods mtobramycine et de la gentamicine monas aeruginosa, other aerobic gramcontre les genres Pseudomonas, The 500 strains of Ps. aeruginosa negative bacilli and Staphylococcus Proteus et Providencia we tested were all isolated from clin¬ aureus. The dosage is the same as that La tobramycine est un nouvel of gentamicin, and similar concentra¬ ical specimens. All except 13 came antibiotique ressemblant a la tions of the two antibiotics are achieved from a larger collection of Ps. aeru¬ gentamicine. Nous avons mesure les in the serum.6'7 The serum half-life of ginosa strains, the gentamicin sensitivi¬ concentrations inhibitrices minimales been previously tobramycin is approximately 2 hours.6 ties of which had series de ces deux antibiotiques contre was selected is cleared from the blood tested.13 The present Tobramycin cinq genres de bacteries qui provoquent by glomerular filtration and reaches from that collection to include all des infections hospitalieres et qui high concentrations in the urine simi¬ strains with a gentamicin minimal in¬ sont resistants a de nombreux lar to those of gentamicin. Pharmaco¬ hibitory concentration (MIC) of 8 kinetic aspects of tobramycin in pa¬ fig/m\ or more and a representative tients with renal impairment8 are simi¬ mixture of strains with MICs of 4, 2 and 1 jjig/ml. Strains with MICs of less lar to those of gentamicin. From the department of microbiology, Sunnybrook. Medical Centre, Toronto and 1 fig/ml were not included, and than such with antibiotic An properties the department of medical microbiology, University of Toronto a wide range of pyocin types14 of Ps. as these would likely be useful in selected to ensure that Reprint requests to: Dr. I.B.R. Duncan, therapeutics only if it were more effec¬ aeruginosa wasnot Microbiology department, Sunnybrook Medical biased by an excess the series was of strains tive than against gentamicin Ont. M4N 3M5 Centre, Toronto, Summary: Tobramycin is a new antibiotic resembling gentamicin. We measured the minimal inhibitory concentrations of these two antibiotics against five bacterial species that cause hospital-acquired infections and are resistant to many presently available antibiotics. The organisms tested were 500 strains of Pseudomonas aeruginosa, 100 strains each of Proteus rettgeri and Pr. morganii, 50 strains of Pr. vulgaris and 250 strains of Providencia stuartii. Tobramycin was 2 to 4 times more active than gentamicin against Ps. aeruginosa) all except 6 of 70 strains resistant to 4 ^g/ml of gentamicin were sensitive to 4 ng/ml of tobramycin. The two antibiotics showed a similar degree of activity against the other four species. Tobramycin promises to be of particular value in the treatment of Pseudomonas infections.
antibiotiques actuellement disponibles. Les organismes soumis aux essais etaient 500 souches de Pseudomonas aeruginosa, 100 souches de Proteus rettgeri et autant de Pr. morganii, 50 souches de Pr. vulgaris et 250 souches de Providencia stuartii. La tobramycine s'est revelee de 2 a 4 fois plus active que la gentamicine contre Ps. aeruginosa; les 70 souches, sauf 6, qui etaient resistantes a 4 ^g/ml de gentamicine etaient sensibles a 4 \ig/m\ de tobramycine. Les deux antibiotiques ont manifeste une activite similaire contre les quatre autres genres de microorganismes. La tobramycine promet d'etre particulierement precieuse dans le traitement des infections a Pseudomonas.
CMA JOURNAL/JULY 12, 1975/VOL. 113 29
of any one type. The remaining 13 strains with MICs of 8 fig/ml or that had been isolated since the original larger series was collected. Of our series of 100 strains of Pr. rettgeri, 69 were type strains from the serotyping system for this organism evolved by Penner, Hinton and Hennessy.15 The other 31 were clinical iso¬ lates from Sunnybrook Medical Centre and these were serotyped by this typing scheme. All 100 strains were derived from human sources except for 3 of the type strains, which were originally isolated from frogs. One hundred strains of Pr. morganii and 50 strains of Pr. vulgaris were isolated from a variety of clinical speci¬ mens from patients at Sunnybrook Medical Centre, Toronto General Hos¬ pital and The Hospital for Sick Chil¬ dren, Toronto. They were obtained from different areas of these hospitals at different times in an attempt to in¬ clude as diverse a group of strains as possible of each species. A total of 250 strains of Prov. stuartii were isolated from clinical spe¬ cimens; 204 were from Sunnybrook Medical Centre, Toronto, and the other 46 came from six other hospitals. All were serotyped on the basis of their O antigens according to the scheme of Ewing, Tanner and Dennard,16 modi¬ fied to include additional antigenic spe¬ cificities designated by one of us were more
No single serotype accounted for more than eight strains. This also is therefore a widely representative collection of strains of the species. Serotyping of the 250 strains of Prov. stuartii showed that the series was less heterogeneous than in the case of the Ps. aeruginosa or the Pr. rettgeri strains. Almost half (112) belonged to the two serotypes of Prov. stuartii (0:4 and 0:63) that were isolated most fre¬ quently from nosocomial infections at Sunnybrook Medical Centre. Of the other 138 strains, 118 were distributed among 21 serotypes, 7 reacted with more than one typing serum, and 13 strains were untypable. The distribution of tobramycin and gentamicin MICs is shown in Table I for all five species of bacteria. The same data are presented in percentage form in Table II to show the propor¬ tion of strains of each species inhibited by concentrations of antibiotic within the range that can be achieved in the serum with therapeutic doses. At each of these values a larger proportion of strains of Ps. aeruginosa was inhibited by tobramycin than by gentamicin. All Table I.Distribution of
the gentamicin-resistant Pseudomonas strains were considerably more sensi¬ tive to tobramycin. Of the 53 with a gentamicin MIC of 8 /tg/ml, 8 had a tobramycin MIC of 1 /ig/ml, 35 had an MIC of 2 fig/ml and 10 an MIC of 4 fig/ml. The tobramycin MICs of the 15 strains with a gentamicin MIC of 16 fjbg/ml were 2 fig/ml in 2, 4 /xg/ml in 9 and 8 fig/ml in 4. The two strains with gentamicin MICs of 64 fig/ml had tobramycin MICs of 16 /xg/ml. Among the 500 strains of Ps. aerugino¬ sa there were 3 with carbenicillin MICs of 512 fig/ml or more; all had tobra¬ mycin MICs of 1 fig/ml and genta¬ micin MICs between 1 and 4 fig/ml. The two antibiotics inhibited all three species of Proteus to almost exactly the same extent (Tables I and II). Strains with a high gentamicin MIC also had a high, and usually identical, tobramycin MIC. With Prov. stuartii somewhat larger percentages were in¬ hibited by tobramycin than by genta¬ micin at the clinically important con¬ centrations 4 and 8 fig/ml. There was a similarly wide spread of MICs among the 112 Prov. stuartii of serotypes 0:4
tobramycin and gentamicin MICs for five bacterial species
(J.L.P.).
Gentamicin sulfate was obtained in form from Schering Corpora¬ tion and tobramycin as a standard solu¬ tion from Eli Lilly & Company. MICs for all the bacteria were estimated by means of an agar dilution method de¬ scribed previously.13 Twofold dilutions of each antibiotic were used in a range from 0.125 to 128 fig/ml. MuellerHinton agar (BBL*) was used as the medium for testing all species except Ps. aeruginosa, for which brain-heart infusion agar was used in conformity with previous work.13
powder
Results
Only 37 of the 500 strains of Ps. Table II.Percentages of each species not be pyocin-typed. tobramycin and gentamicin The typable strains were distributed among 55 distinct pyocin patterns and the numerous type 1 strains were further divisible into 13 subtypes. aeruginosa could
There
were therefore 67 types or sub¬ types in the whole series, which con¬
sequently could be considered a fully representative collection
to be of di¬
strains of Ps. aeruginosa. The 100 strains of Pr. rettgeri were found to include 72 different serotypes.
verse
?Baltimore Biological Laboratories, division of Bioquest Limited. Products are marketed in Can¬ ada by Becton, Dickinson and Company, Ltd., Mississauga, Ont.
30 CMA
JOURNAL/JULY 12, 1975/VOL. 113
inhibited
by various concentrations of
and 0:63 and among the 138 strains of ,.g/ml. In our experience peak blood other types. The two groups were anal- values of 4 to 5 .g/ml are seldom ysed separately, and closely similar re- exceeded in practice with gentamicin stilts were obtained for geometric mean and the same would most likely be MICs and for the proportions of strains true of tobramycin. This would suginhibited by 4 and 8 p.g/ml of each gest that for infections with almost all antibiotic. The large number of strains the Ps. aeruginosa in our large series of these two serotypes did not, there- of clinical isolates, tobramycin alone fore, bias the findings for the full series would be an effective antibiotic. The combination of gentamicin and carbeof 250. The relative activities of gentamicin nicillin is synergistic and may be more and tobramycin against each of the five effective in some infections than gentaspecies are expressed in another way micin alone. The two antibiotics are in Table III by listing numbers of therefore often used together.17 Similar organisms according to the ratio of synergy has been demonstrated in vitro gentamicin MIC to tobramycin MIC between tobramycin and carbenicillin.'8 of each strain. The majority of Proteus Only large-scale clinical trials will show and Providencia strains showed a 1:1 whether tobramycin has real superiratio. The largest group of Pseudo- ority over gentamicin in the treatment monas strains had gentamicin MICs of Pseudomonas infections, but smalltwice their tobramycin MICs. and an- scale investigations already carried out other large group had gentamicin MICs have shown it to be clinically at least four times those of tobramycin. Thus, as effective.'9 of the five species tested, Ps. aeruginoThe results presented in this paper sa was the only one against which to- show that tobramycin and gentamicin bramycin was clearly more active in have equal efficacy against the three vitro than gentamicin. indole-positive species of Proteus. While tobramycin has a marginal advantage over gentamicin against Prov. Discussion si'uartii at the important concentration To justify the addition of a new of 4 ,.g/ml neither antibiotic is very antibiotic to the long list of agents al- effective against this species. We have ready in use, it is necessary to demon- found that, of antibiotics in current strate either improved pharmacologic use, kanamycin is the most likely to be efficacy or wider antibacterial activity. active against the largest number of Tobramycin is so similar pharmaco- Prov. stuartii. Other workers have relogically to gentamicin that the second ported similar findings.20 We have rarerequirement would have to be fulfilled ly isolated the other Providencia spefor tobramycin to be acceptable. cies, Prov. alcalifaciens, and therefore One of the major areas in which there did not investigate its antibiotic sensiis a continuing need for more effec- tivity patterns. Kiebsiella species have tive antibiotics is that of hospital- been an important cause of nosocomial acquired gram-negative infections. Hos- infection at Sunnybrook Medical Cenpital strains of Pseudomonas, indole- tre. We have tested the tobramycin positive Proteus, Providencia, Kieb- sensitivity of only a small number of siella and Serratia are frequently re- recently isolated strains that were resistant to many antibiotics and can be sistant to gentamicin. These isolates very difficult to deal with when they came from seven patients and all beinfect patients whose natural defences longed to one of two types as deterare impaired by complex medical pro- mined by combined biochemical and cedures or serious underlying diseases. serologic typing.2' All had identical toPs. aeruginosa is probably the most bramycin and gentamicin MICs of 8 or troublesome of these organisms, and 16 p.g/ml. Although Serratia marcesour results suggest that tobramycin cens has caused troublesome outbreaks may have distinct advantages over gen- of infection in some hospitals,22 it has tamicin in the treatment of Pseudo- not proved a significant crossinfection monas infections. In vitro at least, problem to us and we have not inmany more strains were inhibited by vestigated its tobramycin sensitivity. tobramycin than by gentamicin at 4 Other investigators' have shown that, Table IiI.-Ratios of gentamicin MIC to tobramycin MIC Species (and number tested) Ps. aeruginosa (500) Pr. rellgeri (100) Pr. morganji (100) Pr. vulgaris (50) Prov. sluarlji (250)
8:1 11
Number of strains with these ratios 4:1 2:1 1:21:4 1:1 181 273 34 1 2 36 53 9 19 70 11 9 35 6 10 72 134 33
in vitro, tobramycin is less active than gentamicin against this organism. It appears that tobramycin has a field of usefulness similar to that of gentamicin and it promises to be particularly valuable against infections due to Ps. aeruginosa. This investigation was supported by a grant from Eli Lilly & Company. We wish to thank Joan Gravelle and Joan Hennessy for their technical assistance in this work and various colleagues for providing bacterial strains. Reference 1. WIcK WE, WELLES JS: Nebramycin, a new broad-spectrum antibiotic complex. IV. In vitro and in vivo laboratory evaluation. Antimicrob Agents Chemother, 1967, p 341 2. KocH KF, RHOADES JA: Structure of nebramycin factor 6, a new aminoglycosidic antibiotic. Antimicrob Agents Chemother, 1970, p 309 3. BLACK HR, GRIFFITH R5: Preliminary studies with nebramycin factor 6. Ibid, p 314
4. DIENSTAG J, Nau HG: In vitro studies of tobramycin, an aminoglycoside antibiotic. Antimicrob Agents Chemother 1: 41, 1972 5. BURGER LM, SANFORD JP, ZWEIGHAFT T: Tobramycin: bacteriological evaluation. Am
J Med Sd 265: 135, 1973
6. REGAMEY C,
GORDON RC, Kiasv WMM:
Comparative pharmacokinetics of tobramycin and gentamicin. Gun Pharmacol Ther 14: 396, 1973
7. KLASTERSKY J, DANEAU D, DE MAERTELAER
V: Comparative study of tobramycin and genmonas activity. Ibid, p 104 tamicin with special reference to antipseudo-
8. JAFFE G, MEYERS BR, HIRSCHMAN SZ: Phar-
macokinetics of tobramycin in patients with stable renal impairment, patients undergoing peritoneal dialysis, and patients on chronic hemodialysis. Antimicrob Agents Chemother 5: 611, 1974 9. PRESTON DA, WICK WE: Preclinical assessment of the antibacterial activity of nebramycin factor 6. Antimicrob Agents Chemother, 1970, p 322
10. DEL BaNE yE, FARRAR WE: Tobramycin: in vitro activity and comparison with kanamycin
and gentamicin. Antimicrob Agents Chemother 1: 340, 1972
11. BaUSCH JL, BARZA M, BERGERON MG, et al: Cross-resistance of Pseudomonas to gentamicin and tobramycin. Ibid, p 280 12. LavIsoN ME, KNIGHT R, KAYE D: In vitro
evaluation of tobramycin, a new aminoglycoside antibiotic. Ibid, p 381 13. DUNCAN IBR: Susceptibility of 1500 isolates of Pseudomonas aerugtnosa to gentamicin, carbenicillin, colistin and polymyxin B. Antimicrob Agents Chemother 5: 9, 1974 14. GOvAN JRW, GILLIES RR: Further studies in the pyocine typing of Pseudomonas pyocyanea. I Med Microbiol 2: 17, 1969
15. PENNER JL, HINTON NA, HENNESSY 3: Sero-
typing of Proteus rettgeri on the basis of 0 antigens. Can I Microbiol 20: 777, 1974 16. EWING WH, TANNER KE, DENNARD DA: The providence group: an intermediate group of enteric bacteria. J infect Dts 94: 134, 1954 17. GARROD LP, LAMBERT HP, 0'GRADY F:.
Antibiotic
and
Edinburgh
and London,
Chemotherapy,
fourth
Churchill
ed.
Living-
stone, 1973, p 83 18. KLUGE RM, STANDIFOan HC, TATEM B, et al: Comparative activity of tobramycin, amikacm, and gentamicin alone and with carbenicillin against Pseudomonas aeruginosa. Antimtcrob Agents Chemother 6: 442, 1974
19. KLASTERSKY 3, HENSGENS C, HENRI A, et al: Comparative clinical study of tobramycin
and gentamicin. Antimicrob Agents Chem-
other 5: 133, 1974 20. REYNOLDS AV, HAMILTON-MILLER
JMT,
BRUMFITT W: Newer aminoglycosides amikacin and tobramycin: an in-vitro comparison with kanamycin and gentamicin. Br Med J 3: 778, 1974 21. RENNIE RP, DUNCAN IBR: Combined biochemical and serological typing of clinical isolates of Kiebsiella. Appi Microbiol 28: 534, 1974
22. MAKI DG, HENNEKENS CG, PHILLIPS CW,
et al: Nosocomial urinary tract infection with Serratia marcescens: an epidemiologic study. I Inject Dis 128: 579, 1973
CMA JOURNAL/JULY 12, 1975/113
31
frcp[c],
frc
path; John L. Penner,
ph d
gram-negative bacilli resistant to pres¬ ently available antibiotics. Tobramycin reportedly has greater activity than gentamicin against Ps. aeruginosa1 and is effective against some strains re¬ sistant to gentamicin.3'9,10 Other inves¬ tigators have reported that gentamicinresistant Ps. aeruginosa strains were also resistant to tobramycin.11 There have also been conflicting reports on the relative activity of the two anti¬ biotics against other nosocomial gramnegative bacilli, such as indole-positive species of Proteus4'12 which are re¬ sistant to many antibacterial agents. The present investigation is an at¬ tempt to resolve some of these discrepancies by testing the comparative activities of the two antibiotics against large collections of Ps. aeruginosa, Pr. The new aminoglycoside antibiotic to¬ rettgeri, Pr. morganii, Pr. vulgaris and bramycin is the most active component1 Providencia stuartii. Strains of three of of nebramycin, a mixture of antimicro¬ these five species were typed to ensure bial substances2 produced by Strepto- that the collection consisted of a widely myces tenebrarius. Its broad antibac¬ representative variety of types. terial spectrum is similar to that of Resume: Activite compare"e de la gentamicin3"5 and it includes Pseudo¬ Materials and methods mtobramycine et de la gentamicine monas aeruginosa, other aerobic gramcontre les genres Pseudomonas, The 500 strains of Ps. aeruginosa negative bacilli and Staphylococcus Proteus et Providencia we tested were all isolated from clin¬ aureus. The dosage is the same as that La tobramycine est un nouvel of gentamicin, and similar concentra¬ ical specimens. All except 13 came antibiotique ressemblant a la tions of the two antibiotics are achieved from a larger collection of Ps. aeru¬ gentamicine. Nous avons mesure les in the serum.6'7 The serum half-life of ginosa strains, the gentamicin sensitivi¬ concentrations inhibitrices minimales been previously tobramycin is approximately 2 hours.6 ties of which had series de ces deux antibiotiques contre was selected is cleared from the blood tested.13 The present Tobramycin cinq genres de bacteries qui provoquent by glomerular filtration and reaches from that collection to include all des infections hospitalieres et qui high concentrations in the urine simi¬ strains with a gentamicin minimal in¬ sont resistants a de nombreux lar to those of gentamicin. Pharmaco¬ hibitory concentration (MIC) of 8 kinetic aspects of tobramycin in pa¬ fig/m\ or more and a representative tients with renal impairment8 are simi¬ mixture of strains with MICs of 4, 2 and 1 jjig/ml. Strains with MICs of less lar to those of gentamicin. From the department of microbiology, Sunnybrook. Medical Centre, Toronto and 1 fig/ml were not included, and than such with antibiotic An properties the department of medical microbiology, University of Toronto a wide range of pyocin types14 of Ps. as these would likely be useful in selected to ensure that Reprint requests to: Dr. I.B.R. Duncan, therapeutics only if it were more effec¬ aeruginosa wasnot Microbiology department, Sunnybrook Medical biased by an excess the series was of strains tive than against gentamicin Ont. M4N 3M5 Centre, Toronto, Summary: Tobramycin is a new antibiotic resembling gentamicin. We measured the minimal inhibitory concentrations of these two antibiotics against five bacterial species that cause hospital-acquired infections and are resistant to many presently available antibiotics. The organisms tested were 500 strains of Pseudomonas aeruginosa, 100 strains each of Proteus rettgeri and Pr. morganii, 50 strains of Pr. vulgaris and 250 strains of Providencia stuartii. Tobramycin was 2 to 4 times more active than gentamicin against Ps. aeruginosa) all except 6 of 70 strains resistant to 4 ^g/ml of gentamicin were sensitive to 4 ng/ml of tobramycin. The two antibiotics showed a similar degree of activity against the other four species. Tobramycin promises to be of particular value in the treatment of Pseudomonas infections.
antibiotiques actuellement disponibles. Les organismes soumis aux essais etaient 500 souches de Pseudomonas aeruginosa, 100 souches de Proteus rettgeri et autant de Pr. morganii, 50 souches de Pr. vulgaris et 250 souches de Providencia stuartii. La tobramycine s'est revelee de 2 a 4 fois plus active que la gentamicine contre Ps. aeruginosa; les 70 souches, sauf 6, qui etaient resistantes a 4 ^g/ml de gentamicine etaient sensibles a 4 \ig/m\ de tobramycine. Les deux antibiotiques ont manifeste une activite similaire contre les quatre autres genres de microorganismes. La tobramycine promet d'etre particulierement precieuse dans le traitement des infections a Pseudomonas.
CMA JOURNAL/JULY 12, 1975/VOL. 113 29
of any one type. The remaining 13 strains with MICs of 8 fig/ml or that had been isolated since the original larger series was collected. Of our series of 100 strains of Pr. rettgeri, 69 were type strains from the serotyping system for this organism evolved by Penner, Hinton and Hennessy.15 The other 31 were clinical iso¬ lates from Sunnybrook Medical Centre and these were serotyped by this typing scheme. All 100 strains were derived from human sources except for 3 of the type strains, which were originally isolated from frogs. One hundred strains of Pr. morganii and 50 strains of Pr. vulgaris were isolated from a variety of clinical speci¬ mens from patients at Sunnybrook Medical Centre, Toronto General Hos¬ pital and The Hospital for Sick Chil¬ dren, Toronto. They were obtained from different areas of these hospitals at different times in an attempt to in¬ clude as diverse a group of strains as possible of each species. A total of 250 strains of Prov. stuartii were isolated from clinical spe¬ cimens; 204 were from Sunnybrook Medical Centre, Toronto, and the other 46 came from six other hospitals. All were serotyped on the basis of their O antigens according to the scheme of Ewing, Tanner and Dennard,16 modi¬ fied to include additional antigenic spe¬ cificities designated by one of us were more
No single serotype accounted for more than eight strains. This also is therefore a widely representative collection of strains of the species. Serotyping of the 250 strains of Prov. stuartii showed that the series was less heterogeneous than in the case of the Ps. aeruginosa or the Pr. rettgeri strains. Almost half (112) belonged to the two serotypes of Prov. stuartii (0:4 and 0:63) that were isolated most fre¬ quently from nosocomial infections at Sunnybrook Medical Centre. Of the other 138 strains, 118 were distributed among 21 serotypes, 7 reacted with more than one typing serum, and 13 strains were untypable. The distribution of tobramycin and gentamicin MICs is shown in Table I for all five species of bacteria. The same data are presented in percentage form in Table II to show the propor¬ tion of strains of each species inhibited by concentrations of antibiotic within the range that can be achieved in the serum with therapeutic doses. At each of these values a larger proportion of strains of Ps. aeruginosa was inhibited by tobramycin than by gentamicin. All Table I.Distribution of
the gentamicin-resistant Pseudomonas strains were considerably more sensi¬ tive to tobramycin. Of the 53 with a gentamicin MIC of 8 /tg/ml, 8 had a tobramycin MIC of 1 /ig/ml, 35 had an MIC of 2 fig/ml and 10 an MIC of 4 fig/ml. The tobramycin MICs of the 15 strains with a gentamicin MIC of 16 fjbg/ml were 2 fig/ml in 2, 4 /xg/ml in 9 and 8 fig/ml in 4. The two strains with gentamicin MICs of 64 fig/ml had tobramycin MICs of 16 /xg/ml. Among the 500 strains of Ps. aerugino¬ sa there were 3 with carbenicillin MICs of 512 fig/ml or more; all had tobra¬ mycin MICs of 1 fig/ml and genta¬ micin MICs between 1 and 4 fig/ml. The two antibiotics inhibited all three species of Proteus to almost exactly the same extent (Tables I and II). Strains with a high gentamicin MIC also had a high, and usually identical, tobramycin MIC. With Prov. stuartii somewhat larger percentages were in¬ hibited by tobramycin than by genta¬ micin at the clinically important con¬ centrations 4 and 8 fig/ml. There was a similarly wide spread of MICs among the 112 Prov. stuartii of serotypes 0:4
tobramycin and gentamicin MICs for five bacterial species
(J.L.P.).
Gentamicin sulfate was obtained in form from Schering Corpora¬ tion and tobramycin as a standard solu¬ tion from Eli Lilly & Company. MICs for all the bacteria were estimated by means of an agar dilution method de¬ scribed previously.13 Twofold dilutions of each antibiotic were used in a range from 0.125 to 128 fig/ml. MuellerHinton agar (BBL*) was used as the medium for testing all species except Ps. aeruginosa, for which brain-heart infusion agar was used in conformity with previous work.13
powder
Results
Only 37 of the 500 strains of Ps. Table II.Percentages of each species not be pyocin-typed. tobramycin and gentamicin The typable strains were distributed among 55 distinct pyocin patterns and the numerous type 1 strains were further divisible into 13 subtypes. aeruginosa could
There
were therefore 67 types or sub¬ types in the whole series, which con¬
sequently could be considered a fully representative collection
to be of di¬
strains of Ps. aeruginosa. The 100 strains of Pr. rettgeri were found to include 72 different serotypes.
verse
?Baltimore Biological Laboratories, division of Bioquest Limited. Products are marketed in Can¬ ada by Becton, Dickinson and Company, Ltd., Mississauga, Ont.
30 CMA
JOURNAL/JULY 12, 1975/VOL. 113
inhibited
by various concentrations of
and 0:63 and among the 138 strains of ,.g/ml. In our experience peak blood other types. The two groups were anal- values of 4 to 5 .g/ml are seldom ysed separately, and closely similar re- exceeded in practice with gentamicin stilts were obtained for geometric mean and the same would most likely be MICs and for the proportions of strains true of tobramycin. This would suginhibited by 4 and 8 p.g/ml of each gest that for infections with almost all antibiotic. The large number of strains the Ps. aeruginosa in our large series of these two serotypes did not, there- of clinical isolates, tobramycin alone fore, bias the findings for the full series would be an effective antibiotic. The combination of gentamicin and carbeof 250. The relative activities of gentamicin nicillin is synergistic and may be more and tobramycin against each of the five effective in some infections than gentaspecies are expressed in another way micin alone. The two antibiotics are in Table III by listing numbers of therefore often used together.17 Similar organisms according to the ratio of synergy has been demonstrated in vitro gentamicin MIC to tobramycin MIC between tobramycin and carbenicillin.'8 of each strain. The majority of Proteus Only large-scale clinical trials will show and Providencia strains showed a 1:1 whether tobramycin has real superiratio. The largest group of Pseudo- ority over gentamicin in the treatment monas strains had gentamicin MICs of Pseudomonas infections, but smalltwice their tobramycin MICs. and an- scale investigations already carried out other large group had gentamicin MICs have shown it to be clinically at least four times those of tobramycin. Thus, as effective.'9 of the five species tested, Ps. aeruginoThe results presented in this paper sa was the only one against which to- show that tobramycin and gentamicin bramycin was clearly more active in have equal efficacy against the three vitro than gentamicin. indole-positive species of Proteus. While tobramycin has a marginal advantage over gentamicin against Prov. Discussion si'uartii at the important concentration To justify the addition of a new of 4 ,.g/ml neither antibiotic is very antibiotic to the long list of agents al- effective against this species. We have ready in use, it is necessary to demon- found that, of antibiotics in current strate either improved pharmacologic use, kanamycin is the most likely to be efficacy or wider antibacterial activity. active against the largest number of Tobramycin is so similar pharmaco- Prov. stuartii. Other workers have relogically to gentamicin that the second ported similar findings.20 We have rarerequirement would have to be fulfilled ly isolated the other Providencia spefor tobramycin to be acceptable. cies, Prov. alcalifaciens, and therefore One of the major areas in which there did not investigate its antibiotic sensiis a continuing need for more effec- tivity patterns. Kiebsiella species have tive antibiotics is that of hospital- been an important cause of nosocomial acquired gram-negative infections. Hos- infection at Sunnybrook Medical Cenpital strains of Pseudomonas, indole- tre. We have tested the tobramycin positive Proteus, Providencia, Kieb- sensitivity of only a small number of siella and Serratia are frequently re- recently isolated strains that were resistant to many antibiotics and can be sistant to gentamicin. These isolates very difficult to deal with when they came from seven patients and all beinfect patients whose natural defences longed to one of two types as deterare impaired by complex medical pro- mined by combined biochemical and cedures or serious underlying diseases. serologic typing.2' All had identical toPs. aeruginosa is probably the most bramycin and gentamicin MICs of 8 or troublesome of these organisms, and 16 p.g/ml. Although Serratia marcesour results suggest that tobramycin cens has caused troublesome outbreaks may have distinct advantages over gen- of infection in some hospitals,22 it has tamicin in the treatment of Pseudo- not proved a significant crossinfection monas infections. In vitro at least, problem to us and we have not inmany more strains were inhibited by vestigated its tobramycin sensitivity. tobramycin than by gentamicin at 4 Other investigators' have shown that, Table IiI.-Ratios of gentamicin MIC to tobramycin MIC Species (and number tested) Ps. aeruginosa (500) Pr. rellgeri (100) Pr. morganji (100) Pr. vulgaris (50) Prov. sluarlji (250)
8:1 11
Number of strains with these ratios 4:1 2:1 1:21:4 1:1 181 273 34 1 2 36 53 9 19 70 11 9 35 6 10 72 134 33
in vitro, tobramycin is less active than gentamicin against this organism. It appears that tobramycin has a field of usefulness similar to that of gentamicin and it promises to be particularly valuable against infections due to Ps. aeruginosa. This investigation was supported by a grant from Eli Lilly & Company. We wish to thank Joan Gravelle and Joan Hennessy for their technical assistance in this work and various colleagues for providing bacterial strains. Reference 1. WIcK WE, WELLES JS: Nebramycin, a new broad-spectrum antibiotic complex. IV. In vitro and in vivo laboratory evaluation. Antimicrob Agents Chemother, 1967, p 341 2. KocH KF, RHOADES JA: Structure of nebramycin factor 6, a new aminoglycosidic antibiotic. Antimicrob Agents Chemother, 1970, p 309 3. BLACK HR, GRIFFITH R5: Preliminary studies with nebramycin factor 6. Ibid, p 314
4. DIENSTAG J, Nau HG: In vitro studies of tobramycin, an aminoglycoside antibiotic. Antimicrob Agents Chemother 1: 41, 1972 5. BURGER LM, SANFORD JP, ZWEIGHAFT T: Tobramycin: bacteriological evaluation. Am
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macokinetics of tobramycin in patients with stable renal impairment, patients undergoing peritoneal dialysis, and patients on chronic hemodialysis. Antimicrob Agents Chemother 5: 611, 1974 9. PRESTON DA, WICK WE: Preclinical assessment of the antibacterial activity of nebramycin factor 6. Antimicrob Agents Chemother, 1970, p 322
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evaluation of tobramycin, a new aminoglycoside antibiotic. Ibid, p 381 13. DUNCAN IBR: Susceptibility of 1500 isolates of Pseudomonas aerugtnosa to gentamicin, carbenicillin, colistin and polymyxin B. Antimicrob Agents Chemother 5: 9, 1974 14. GOvAN JRW, GILLIES RR: Further studies in the pyocine typing of Pseudomonas pyocyanea. I Med Microbiol 2: 17, 1969
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typing of Proteus rettgeri on the basis of 0 antigens. Can I Microbiol 20: 777, 1974 16. EWING WH, TANNER KE, DENNARD DA: The providence group: an intermediate group of enteric bacteria. J infect Dts 94: 134, 1954 17. GARROD LP, LAMBERT HP, 0'GRADY F:.
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